Characteristics of adrenergic receptors.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"217",leadTitle:null,fullTitle:"Recent Trends in Processing and Degradation of Aluminium Alloys",title:"Recent Trends in Processing and Degradation of Aluminium Alloys",subtitle:null,reviewType:"peer-reviewed",abstract:"In the recent decade a quantum leap has been made in production of aluminum alloys and new techniques of casting, forming, welding and surface modification have been evolved to improve the structural integrity of aluminum alloys. \nThis book covers the essential need for the industrial and academic communities for update information. It would also be useful for entrepreneurs technocrats and all those interested in the production and the application of aluminum alloys and strategic structures. It would also help the instructors at senior and graduate level to support their text.",isbn:null,printIsbn:"978-953-307-734-5",pdfIsbn:"978-953-51-6077-9",doi:"10.5772/741",price:159,priceEur:175,priceUsd:205,slug:"recent-trends-in-processing-and-degradation-of-aluminium-alloys",numberOfPages:530,isOpenForSubmission:!1,isInWos:1,hash:"6b334709c43320a6e92eb9c574a8d44d",bookSignature:"Zaki Ahmad",publishedDate:"November 21st 2011",coverURL:"https://cdn.intechopen.com/books/images_new/217.jpg",numberOfDownloads:114699,numberOfWosCitations:106,numberOfCrossrefCitations:32,numberOfDimensionsCitations:109,hasAltmetrics:0,numberOfTotalCitations:247,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 20th 2010",dateEndSecondStepPublish:"November 17th 2010",dateEndThirdStepPublish:"March 24th 2011",dateEndFourthStepPublish:"April 23rd 2011",dateEndFifthStepPublish:"June 22nd 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"52898",title:"Prof.",name:"Zaki",middleName:null,surname:"Ahmad",slug:"zaki-ahmad",fullName:"Zaki Ahmad",profilePictureURL:"https://mts.intechopen.com/storage/users/52898/images/1942_n.jpg",biography:"Professor Dr. Zaki Ahmad worked at King Fahd University of Petroleum and Minerals for thirty years in rendered distinguished services in teaching and research. He obtained his PhD from LEEDS University, UK. He was a chartered metallurgical engineer (C.Eng) from engineering council UK. He was a fellow of the institute of Materials, Minerals and Mining(FIMMM). He was a member of the European federation of corrosion and a fellow of institute of Metal Finishing. He substantially contributed to the founding activities in material science, corrosion engineering and nanotechnology at KFUPM and in Iran. He worked on international projects on aluminum with Aluminum, Ranshofen, Austria and Forschungzentrum, Geethscht, Germany and with Metallgesselscheft, Germany. He worked on international projects with Ministry of Technology, Germany. He was a founder contributor of center of excellence in corrosion at KFUPM, Dhahran, Saudi Arabia. He worked on the foundation and development of nanotechnology in Saudi Arabia in 2004. He was the author of “Principles of Corrosion Engineering and Corrosion Control” published by Elsevier in 2006. He has written over 95 research papers and international journals and over forty papers in international research conferences. His research activities included development of Al/SC alloys, Nanostructured superhydrophrobic surfaces, Nanocoatings and self-healing techniques. He was nominated for best researcher award in the Middle East by Energy Exchange in 2011. 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This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. I am responsible for developing and maintaining strong relationships with all collaborators to ensure an effective and efficient publishing process and support other departments in developing and maintaining such relationships."}},relatedBooks:[{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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The prevalence of ALL in patients >60 years of age is reported to be between 16 and 31% of all adult cases. In adults, it represents approximately 20% of all leukemia [1].
\nThe age-adjusted incidence rate of ALL in the United States is 1.58 for every 100,000 persons per year. About 57.2% of the patients diagnosed are under 20 years of age, 26.8% of patients diagnosed are over 45 years of age, and 11% of patients diagnosed are over 65 years of age [2]. The biology of ALL in older patients seems to be significantly different from that in younger patients and may, at least in part, explain the poor treatment outcome. Immunophenotyping and cytogenetic characteristics are among the most important biological differences in comparison with younger adults. The frequency of pre-B-cell ALL and common ALL is higher, and T-cell ALL subtype is under-represented in elderly populations compared with younger patients. The frequency of the Philadelphia chromosome also seems to increase with age and adversely influences complete remission rate and survival. Few reports on the effectiveness and toxicity of therapeutic programs concerning exclusively older patients with ALL have been published so far and only some of them were prospective studies [3].
\nIn some of the studies, age-adapted approaches have been applied in which protocols processed earlier for younger patients have been adopted for older patients. In such modified protocols, chemotherapy was usually less aggressive, especially if it was given for patients with comorbidities and poor performance status. Consequently, in several studies, elderly patients received suboptimal treatment. Death during induction chemotherapy was observed in 7–42% of the patients in particular reports. The overall response rate varied from 12 to 85%. The median overall survival (OS) durations in patients who received a curative approach ranged from 3 to 14 months and from 1 to 14 months in patients treated with palliative therapy. Poor performance status, comorbidities, and high early mortality during intensive chemotherapy are the main reasons for poor treatment results and short OS time. New therapeutic approaches are necessary to improve the outcome in this age group of patients with ALL [4].
\nThe implementation of tools aimed to determining the safety of treatments in elderly patients based on protocols that have previously been applied and validated in younger patients is a common practice today. A recently identified problem when applying these tasks is the underutilization of treatments with curative purposes in this group. An example of this is the CIRS-G scale, widely used to determine the risk of complications in patients with various comorbidities [4]. This phenomenon has been recorded in various efficacies and safety analyzes of treatment for acute lymphoblastic leukemia in elderly patients based on similar scales, where an important survival difference has been observed between the groups treated for curative purposes and those who received reduced therapy. Of course, comorbidities play an important role in these poor results, which forces us to search for new therapeutic options [5].
\nThe clonal origin of ALL has been established using cytogenetic analysis; restriction fragment analysis in female patients, which are heterozygous for polymorphic genes linked to the X chromosome; and analysis of T-cell receptor or immunoglobulin gene rearrangements. The clinical manifestations are very variable and insidious. The symptoms generally reflect bone marrow failure characterized by four syndromes: anemia, hemorrhage, febrile, and infiltrative. Nearly, half of the patients present with some kind of infectious process at diagnosis. Bone infiltration may produce pain and arthralgia. Additionally, close to half the patients have hepatomegaly or splenomegaly [5].
\nThe long-term survival of older adults with acute lymphoblastic leukemia (ALL) who are intensively treated is about 40% [1]. Hematologic remissions are obtained in over 90% of patients, and the depth of these remissions using flow cytometry and molecular techniques is the subject of current studies. It is likely that, with time, new response definitions based on these tests will be established. The adult patients were divided into age 30 years and 30–60 years, because this seemed clinically relevant, and available data best dealt with these age categories. However, these divisions are not absolute or evidence-based, and an individual’s biologic age and general fitness are of paramount importance. There are no randomized studies in older adults that demonstrate “pediatric” approaches to be superior, and indeed, the single-arm studies are still small scale in this age group, with insufficient follow-up. Much is unknown, but the wide variety of trials being conducted in adults with ALL is heartening [6].
\nThe development of ALL is driven by successive mutations that alter cellular functions promoting
greater ability for self-renewal,
greater proliferation,
blockage of differentiation, and
resistance to apoptotic signals.
Different hereditary DNA repair disorders can play an important role in the induction of this disease. Furthermore, mutagenic environmental agents, which can be physical (ionizing radiation), chemical (benzene), and biological (HTLV-1), can also be involved. However, in most cases, there are no identifiable etiologic agents. The precise pathogenic events that lead to the development of ALL are unknown. About 5% of the cases are associated with genetic predisposition syndromes. This is the case for children with Down syndrome, who have a 10–30 times greater risk of leukemia and present genetic abnormalities such as hyperdiploidy and t (12; 21) [ETV6-RUNX1], +X, del (9), and alteration in CCAAT//enhacer-binding protein beta (CEBPD). It has been demonstrated that the fusion of P2RY8-CRLF2 and the activation of JAK mutations contribute to 50% of the ALL cases in patients with Down syndrome. Ninety percent have a deletion of IKZF12015. The disorders associated with chromosomal fragility that have been found to predispose to ALL include ataxia-telangiectasia, Nijmegen syndrome, and Bloom syndrome [7]. Patients with ataxia-telangiectasia have 70 times greater risk of leukemia and 250 times greater risk of lymphoma, particularly of T cells. The causal gene, ataxia-telangiectasia mutated (ATM), encodes a protein implicated in DNA repair and regulation of cellular proliferation and apoptosis [2, 7, 8]. Complete genome sequencing studies have identified a number of common allelic variants in four genes (IKZF1, ARID5B, CEBPE, and y CDKN2A) associated with infant ALL. The allelic variant inherited can affect the response to treatment. In utero exposure to X-rays for diagnostic use can confer a slight increase in risk for ALL, which positively correlates with exposure intensity. Data exist that support a causal role for polymorphisms in genes that encode antioxidant enzymes (for example: glutathione S-transferase, nicotinamide adenine dinucleotide phosphate (NADPH), quinone oxidoreductase), folate metabolic enzymes (serine hydroxymethyltransferase and thymidylate synthase), cytochrome 450, methylenetetrahydrofolate reductase, and cell cycle inhibitors [3, 5, 8, 9]. Specific fusion genes have been identified in leukemia, the most noteworthy being KMT2A/AFF1 (also known as MLL-AF4) and ETV6-RUNX1 or TEL-AML1; additionally, there is hyperploid and rearrangements of immunoglobulin or T-cell receptor genes. The acquired genetic anomalies are a hallmark, 80% of all cases contain cytogenetic or molecular lesions with abnormalities in chromosome number (ploidy) and structure. The mechanisms involved include aberrant expression of oncoproteins, loss of tumor suppressor genes, and chromosomal translocations, which generate fusion genes that encode transcription factors of active kinases. A single genetic rearrangement is not enough to induce leukemia. Cooperative mutations are necessary for leukemic transformation and include genetic and epigenetic changes in regulatory growth pathways. Candidate genes identified include deletion of the tumor suppressor locus CDKN2A/CDKN2B and NOTCH1 mutations in T cells. The use of single nucleotide polymorphism (SNP) microarrays suggests that genomic instability is not characteristic of most cases. There is a great variation in the number of alterations in different subtypes of leukemia. The infant cases with rearrangements of the MLL gene had less than one copy number alterations (CNA) per case, suggesting that few genetic lesions are required. Conversely, cases with ETV6-RUNX1 [25] and BCR-ABL1 had more than six CNAs, some containing more than 20 lesions, which support the concept that despite the initiating events that may occur in early infancy, additional lesions are required for the subsequent development of ALL. The lymphoid transcription factor PAX5 encodes a protein involved in evolution and fidelity of the B-cell lineage. The second most frequently affected gene was IKZF1, which encodes the protein IKAROS, required for lymphoid differentiation. IKZF1 is absent in most cases with BCR-ABL1. Approximately, half of the patients expressing BCRABL1 also had deletions in CDKN2A/B and PAX5. This finding suggests that alterations in different signaling pathways are needed to induce leukemia [15]. A special role in this disease is played by the presence of the Philadelphia chromosome t (9; 22), which expresses the BCR-ABL fusion gene, and this has diagnostic, prognostic, and therapeutic implications [3, 6, 7, 8, 9, 10, 11].
\nThe bone marrow aspiration test is fundamental to confirm the presence of lymphoblasts (by morphology and/or cytochemistry with special stains that include a negative MPO in 100% of cells, Periodic Acid-Shiff (PAS) (+) in 70–80%, and acid phosphatase (+) in the case of T lymphoblast). The WHO suggests greater than 20% as diagnosis criteria (if the percentage is lower, one must search for extramedullary disease at the nodal level to differentiate from the diagnosis of lymphoblastic lymphoma). The bone marrow aspiration is hypercellular 95–100% of the time; however, in those cases where the aspirate is “dry” (packed bone marrow), which corresponds to 1–2% of the cases, a bone biopsy must be carried out for histopathological confirmation. Based on morphology, the French-American-British (FAB) classification identifies three types of ALL [7, 8, 12].
\n\n
The first step to integrate the diagnosis of ALL is the morphological identification of lymphoblasts. For this, it is necessary to perform a bone marrow aspirate and be observed directly under a microscope by an expert in hematology, which can be supported in other tests like special stains, as in the case of myeloperoxidase, which must be negative in all the malignant cells observed; PAS staining, which is considered positive for ALL when observed in 70–80% of cells with malignant morphology and acid phosphatase, which is used for T-cell differentiation. Regarding manual cell counting, it is necessary that the presence of 20% or more cells with malignant characteristics, as indicated by the criteria of the WHO classification, in case this criterion is not met, can be replaced by others such as the documentation of extramedullary disease. It is important to specify that most of the times, we may have difficulties in trying to obtain the sample for the bone marrow aspirate, since the large number of cells within the medullary space condition the presence of the phenomenon of “dry” aspiration; in these cases, we must carry out bone biopsy in a mandatory manner.
\nThe French-American-British (FAB) classification that was used commonly earlier includes:
L1—around 25–30% of adult cases and 85% of childhood cases of ALL are of this subtype. In this type, small cells are seen with:
regular nuclear shape
homogeneous chromatin
small or absent nucleolus
scanty cytoplasm
L2—around 70% of adult cases and 14% of childhood cases are of this type. The cells are large and/or have varied shapes with:
irregular nuclear shape
heterogeneous chromatin
large nucleolus
L3—this is a rarer subtype with only 1–2% cases. In this type, the cells are large and uniform with vacuoles (bubble-like features) in the cytoplasm overlying the nucleus.
In an initial effort, the French-American-British (FAB) was given the task of sub-classifying this type of leukemia according to various morphological characteristics in order to try to determine the behavior and prognosis of each type based on its morphology; this is how the FAB morphological classification was born, which subdivides the ALL into three types:
L1: this subtype is characterized by presenting cells with a regular nucleus, homogeneous chromatin, small or absent nucleoli, and scarce cytoplasm. It represents the majority of the ALL in children observed in up to 85%, while in adults, it is seen between 30% and 70% of the times.
L2: unlike the previous one, this subclassification is seen mostly in adults (70%) and its morphology is opposite to L1: chromatin is heterogeneous, the nucleus irregular, and with multiple nucleoli.
L3: the least frequent of the three, is reported between 1 and 2% of the time. Its main characteristic is the large number of vacuoles (bubbles) that these cells present in their cytoplasm. The shape of the nucleus may vary.
WHO proposed a classification of ALL that was to be the revised version of the FAB classification.
\nThis used the immunophenotypic classification that includes:
Acute lymphoblastic leukemia/lymphoma or formerly L1 and L2 this has subtypes including:
precursor B acute lymphoblastic leukemia/lymphoma: this has genetic subtypes including t(12,21)(p12,q22) TEL/AML-1, t(1,19)(q23;p13) PBX/E2A, t(9,22)(q34;q11) ABL/BCR and T(V,11)(V;q23) V/MLL
precursor T acute lymphoblastic leukemia/lymphoma
Burkitt’s leukemia/lymphoma or formerly L3
biphenotypic acute leukemia
The WHO performed a new categorization of acute lymphoblastic leukemia, based on cytogenetic alterations present in this disease. This classification considered what was previously described in the FAB classification being possible to make an indirect correlation between the morphological findings and the alterations listed in the categories of the WHO classification. In this way, those leukemias that are traditionally classified in the FAB groups L1 and L2 can belong to the group of leukemia of precursors B with alterations such as: t (12; 21) (p12, q22) TEL/AML-1, t (1; 19) (q23; p13) PBX/E2A, t (9; 22) (q34; q11) ABL/BCR, and T (V, 11) (V; q23) V/MLL. Those traditionally classified as FAB L3 correlate with Burkitt’s leukemia/lymphoma; T-cell leukemias are still an independent group and are considered another group where those that meet criteria for two different lineages are included.
\nThe proportion of B-lineage ALL is higher in patients older (75–89%) than 60 years compared to patients younger (59–66%) than 60 years. Accordingly the incidence of T-ALL is lower in older (8–12%) compared to younger (29%) patients [5, 6, 7]. A population-based study showed that cytogenetics were less frequently attempted in older (73%) compared with younger (85–91%) patients. The proportion of patients with Philadelphia chromosome positive (Ph+) t(9;22), t(8;14), t(14;18), or complex aberrations increased with age [11]; Ph+ ALL accounted for 24–36% in older patients vs. 15–19% in younger patients. Considering the consequences resulting from diagnostic characterization, it should be self-evident that complete diagnostic characterization is required in all patients with ALL, regardless of age [13, 14].
\nThere are several important differences in the biology of lymphoblastic leukemia in patients over 60 years compared to those under this age, although we know that B-lineage leukemia is the most common in adults, the frequency between both groups can vary reporting a little more frequent in those over 60 years (75–89%/59–66%), another more radical difference is the presentation of leukemia of T lineage, which is more common in adults under 60 years (29%) than in elderly patients (12%) [5, 6, 7]. Cytogenetic alterations of importance for the prognosis, such as Philadelphia chromosome (Ph+) t (9; 22), t (8; 14), t (14; 18), or complex karyotype are observed more frequently as the patient’s age increases [11]. Although the search for cytogenetic alterations is crucial to define the risk and possible response to treatment of acute leukemia, this analysis is not carried out in most elderly patients (73%), contrary to the young patients, who have available cytogenetic studies in up to 91%. The importance of this difference lies in the fact, already mentioned, of the increase in the frequency of high-risk alterations, as an example Ph+ ALL can be found in up to 36% of cases, which have different therapeutic approaches to those that do not suffer from this alteration [13, 14].
\nAs in other B-cell malignancies, monoclonal antibodies to CD20 or CD228 are being tested as adjuncts to chemotherapy in the hope that they will increase remission depth and improve survival without increasing hematologic toxicity. About 60–80% of B-cell ALL patients express these antigens at variable densities, but there is little evidence linking antigen expression to response. CD20 expression may be associated with a worse prognosis, so it is logical to investigate CD20 antibodies in randomized trials, and it may improve the outcome [15, 16].
\nBlasts in pre-B ALL can be initially identified using an SSC vs. a CD45 plot. These blasts have low SSC (many times smaller than normal lymphocytes) and dim to negative CD45.
\n\n
Once the blasts are identified and gated, the following markers are useful in the classification of pre-B ALL:
Marker | \nPrevalence | \n
---|---|
CD10 | \n89% | \n
CD13 | \n5% | \n
CD19 | \n100% | \n
CD20 | \n24% | \n
CD22 | \n69% | \n
CD33 | \n31% | \n
CD34 | \n76% | \n
CD45 (bright) | \n2% | \n
CD45 (moderate) | \n33% | \n
CD45 (dim) | \n36% | \n
CD45 (negative) | \n29% | \n
CD56 | \n36% | \n
CD79a | \n88% | \n
CD117 | \n0% | \n
Cytoplasmic IgM | \n22% | \n
HLA Dr | \n98% | \n
TdT | \n91% | \n
\n
Included are marking prevalences.
\nThe phenotype of the blasts is an independent prognostic parameter. B-ALL is subdivided into following:
Early Pre-B ALL: TdT+, CD19+, CD10-
Common ALL: CD19+, CD10+/CALLA+
Pre-B ALL: CD10+/−, CD19+, HLA DR+, cytoplasmic IgM+
Mature B ALL: CD10+, CD19+, CD20+, CD22+, surface IgM+
T-cell ALL constitutes approximately 25% of all adult cases of ALL. T-cell markers are CD1a, CD2, CD3 (membrane and cytoplasm), CD4, CD5, CD7, and CD8. CD2, CD5, and CD7 antigens are markers of the most immature T cells, but none of them is absolutely lineage-specific, so that the unequivocal diagnosis of T-ALL rests on the demonstration of surface/cytoplasmic CD3. In T-ALL, the expression of CD10 is quite common (25%) and not specific; CD34 and myeloid antigens CD13 and/or CD33 can be expressed too. Recognized T-ALL subsets are the following: pro-T EGIL T-I (cCD3+, CD7+), pre-T EGIL T-II (cCD3+, CD7+, and CD5/CD2+), cortical T EGIL T-III (cCD3+, CD1a+, and sCD3+/−), and mature-T EGIL T-IV (cCD3+, sCD3+, and CD1a−). Finally, a novel subgroup that was recently characterized is represented by the so-called ETP-ALL (early-T precursor), which shows characteristic immunophenotypic features, namely lack of CD1a and CD8 expression, weak CD5 expression, and expression of at least one myeloid and/or stem cell marker [17].
\nWith currently refined diagnostic techniques, the occurrence of acute leukemia of ambiguous cell lineage, i.e., mixed phenotype acute leukemia (MPAL) is relatively rare (<4%) [19]. These cases express one of the following feature: (1) coexistence of two separate blast cell populations (i.e., T- or B-cell ALL plus either myeloid or monocytic blast cells), (2) single leukemic population of blast cells co-expressing B- or T-cell antigens and myeloid antigens, and (3) same plus expression of monocytic antigens. For myelo-monocytic lineage, useful diagnostic antigens are MPO or nonspecific esterase, CD11c, CD14, CD64 and lysozyme; for B-lineage, CD19 plus CD79a, cytoplasmic CD22 and CD10 (one or two of the latter according to staining intensity of CD19); and for T-lineage, cytoplasmic or surface CD3. Recognized entities include Ph+ MPAL (B/myeloid or rarely T/myeloid), t(v;11q23); MLL rearranged MPAL, and genetically uncharacterized B or T/myeloid MPAL. Very rare cases express trilineage involvement (B/T/myeloid). Lack of lineage-specific antigens (MPO, cCD3, cCD22) is observed in the ultrarare acute undifferentiated leukemia. In a recent review of 100 such cases, 59% were B/myeloid, 35% T/myeloid, 4% B/T lymphoid, and 2% B/T/myeloid. Outcome was overall better following ALL rather than AML therapy [7, 16, 18, 19].
\nCD56, a marker of natural killer (NK) cell differentiation, defines a rare subgroup of about 3% of adult ALL cases, which often display other early T-cell antigens, CD7 CD2 CD5, and sometimes cCD3. True NK ALL is very rare (TdT+, CD56+, other T markers negative, and un-rearranged TCR genes). This diagnosis rely on the demonstration of early NK-specific CD94 or CD161 antigens [18, 19].
\nCytogenetics represents an important step in ALL classification. Conventional karyotyping can be helpful in the identification of recurrent translocations, as well as gain and loss of gross chromosomal material; however, the major limitation of this technique is that in some cases, leukemic cells fail to enter metaphase. However, fluorescence in situ hybridization (FISH) can enable the detection and direct visualization of virtually all investigated chromosomal abnormalities in ALL, with a sensitivity of around 99%. Finally, array-comparative genomic hybridization (array-CGH, a-CGH) and single nucleotide polymorphisms (SNP) arrays can permit the identification of cryptic and/or submicroscopic changes in the genome. Karyotype changes found in ALL include both numerical and structural alterations, which have profound prognostic significance. With these premises in mind, the karyotype changes that occur in ALL can be roughly subdivided in those associated, respectively, with a relatively good, intermediate, and poor prognosis. However, it must be kept in mind that the incidence of certain aberrations is very low, and that for some of them, the prognostic impact can be strongly affected by the type and intensiveness of therapy administered [8, 20].
\nFeatures associated with large tumor mass or rapid progression, such as high white blood cell count, mediastinal tumors, or other organ involvement, appear to be less common in older patients. Even “smoldering” ALL is observed in some cases. Most studies report a lower proportion of males among older ALL patients. Secondary ALL after myelodysplastic syndromes or other malignant disease may become increasingly important, particularly in older patients; so far, very limited data are available. Performance status often deteriorates in older patients with onset of disease. In two studies, 30–43% of patients older than age 60 years vs. 18–22% of younger patients had a performance status of 2 or more. Therefore, it is important not only to consider the current general condition in newly admitted older ALL patients but also to discern their status before the onset of leukemia-associated symptoms [17, 21].
\nThe determination of the clinical status at the moment of making the diagnosis provides us with information about the global state of the patient, so that we can make better decisions. This varies in comparison with the younger groups in questions such as the low initial presentation of large tumor mass, identified by the elevated white blood cells count in the peripheral blood, the rare extranodal affection and even in some cases being observed, apparently “benign” clinical presentation with low tumor burden. A smaller proportion of male patients in this group have also been observed as compared with younger groups. Secondary leukemia, which we define as that which occurs after a premalignant pathology, most frequently myelodysplastic syndrome, or after treatment of nonhematological neoplasms, is a condition that has been observed more and more frequently in recent years. However, there is little data to help us determine its nature. It is important to assess these patients comprehensively in order to determine their physical and health status prior to the onset of symptoms related to leukemia [17, 21].
\nOf older ALL patients, 60–70% suffer from comorbidities, but most studies did not refer to validated scoring systems. The German multicentre study group for adult ALL (GMALL) identified comorbidities according to the Charlson score in 84% of the patients older than 55 years, with diabetes (46%), vascular disease (18%), heart failure (15%), and chronic lung disease (12%) being the most frequent. In addition, renal insufficiency, anemia, osteoporosis, dementia, and depression are probably the most relevant comorbidities for potential adjustment of treatment. About 8–16% had a history of prior malignant disease. I recommend a systematic evaluation and documentation of comorbidities based on a checklist or a score, since this is essential for planning an optimal treatment strategy [4, 5, 18, 23].
\nComorbidities in elderly patients with ALL require a specialized and detailed approach. The German multicentre study group for adult ALL (GMALL) recommends the use of the Charlson scale for the determination of risk due to comorbidities; this assessment must be done in an integral manner, together with the physics, biochemistry, and cytomolecular evaluation of the disease [4]. Multiple systemic diseases can afflict elderly patients with ALL: diabetes, hypertension, heart failure, and renal failure are some of the most frequently reported in the various studies conducted. Age-specific conditions such as dementia or osteoporosis that can negatively impact the patient’s performance before and after treatment should not be left aside. It is also important to evaluate, monitor and, if necessary, treat alterations in the emotional state of the elderly patient, since depression and anxiety are not infrequent conditions in this group [5, 18, 22].
\nNow, we have a better understanding of the factors that determine survival, but these will require reexamination as we introduce novel therapies. Cytogenetic findings such as Philadelphia chromosome positivity, t (4; 11), complex cytogenetic abnormalities (more than five chromosomal changes), and low hypodiploidy/near triploidy result in inferior survival. Some of these changes are more common in older adults. Other conventional factors such as increasing age, high white blood cell count, and B-cell disease (rather than T-cell disease) still hold true and predict higher failure rates with standard chemotherapy. However, many of these factors are also associated with a higher relapse rate after allografting, and it is not necessarily the case that bone marrow transplantation (BMT) is the solution for patients with adverse prognostic features. Combining these factors may allow individualization of therapy, a prospect not previously possible in this rare condition. As well as undertreating patients with ALL with chemotherapy that is likely to fail, prognostic factors should be used to avoid over treating better prognosis patients with allogeneic transplants that have a high upfront risk and may result in chronic graft-versus host disease (GVHD), infertility, and secondary malignancy. Chemotherapy and transplant have complementary roles in ALL management, and a pragmatic approach is required to deliver the best outcomes. The role of BMT is likely to increase, especially with the promising results of reduced-intensity allografting, but conversely, the use of BMT should be reduced if advances in nontransplant therapy improve cure rates [11, 17, 20, 23].
\nIncreasing age itself is one of the most relevant prognostic factors for outcome of ALL from childhood to old age. Since older patients show opposite problems, namely higher mortality and relapse rates, prognostic factors for both have to be analyzed. Prognostic factors for relapse risk in younger ALL patients are probably also valid in older patients, such as early and mature T-ALL, pro-B ALL, elevated white blood cell count, and Ph+ ALL; however, their predictive value is somewhat diluted by mortality risks. Evaluation of minimal residual disease (MRD) has demonstrated that persistence of MRD is associated with a relapse rate above 90% in younger patients despite continued intensive chemotherapy. Few data on the prognostic impact of MRD are available in older patients. In one study, only 11% of the older patients with molecular failure after first consolidation remained in complete response (CR) compared with 68% of those with molecular remission. In older patients with less intensive therapy, a higher rate of MRD persistence and an even poorer outcome can be expected. Therefore, prospective evaluation of MRD in older patients is essential to identify those who could benefit from alternative experimental treatments, if they were available [18, 19, 20, 24].
\nSome poor prognosis factor applicable to young patients can also be in elderly patients, which tells us of the profound impact they have on the biology of the disease: the T lineage and the positive Phi chromosome are a pair of these. The persistence of positive minimal residual disease is directly related to an increased frequency of relapse after remission; it is estimated that young patients with positive MRD will relapse up to 90% despite receiving intensive CT. We do not have such exact estimates of how much the likelihood of relapse increases when this phenomenon occurs in older patients, but it has been estimated in some studies that only 11% of these who presented with MRD positive remain in response to the disease. Prospective studies that answer these questions are required; however, it is necessary to determine MRD in elderly patients as part of the management and surveillance protocols [18, 19, 20, 23].
\nIn the GMALL study for older patients, we identified comorbidity score, age, and performance status before onset of leukemia as prognostic factors with significant impact on early mortality. Interestingly, Eastern Cooperative Oncology Group (ECOG) status of 2 or more was documented in 7% of the patients before onset of leukemia-associated symptoms, but in 38% after onset. The strong correlation of performance status with mortality was confirmed by others.
\nFor assessing prognosis in an older ALL patient, it is essential to identify features suitable for predicting high risk of early mortality resulting from complications. These features can help determine whether a patient has any chance of benefiting from intensive treatment. For this purpose, I would consider performance status before onset of leukemia, comorbidities, and geriatric assessment and would not rely on scores, which are calculated on the basis of historical patient cohorts.
\nIn addition, prognostic factors for response to antileukemic treatment and relapse risk must be considered. Because of the lack of confirmed prognostic factors for older ALL patients, my approach would be to take known prognostic factors for younger patients into consideration, but to focus on MRD evaluation as an individual prognostic feature that can cover the impact of biologic factors and also treatment intensity, compliance, and other unknown features [21, 26].
\nIn the case of patients with characteristics that could increase the risk of early mortality when starting treatment, we must be careful in how to approach this last parameter. Several groups dedicated to the analysis of prognostic factors in special groups of patients have determined a series of variants and elements that could guide the clinic when defining the risk of death of his patient. The GMALL group determined, in a prospective analysis, that the low physical status (ECOG status of 2 or more) prior to the onset of leukemia symptoms correlates with earlier mortality and in those patients who already have a diagnosis, this score is seen duplicated at the beginning of the symptomatology. To be able to carry out a complete evaluation of elderly patients, it is necessary to apply tools that are useful in most clinical scenarios and that confer a high degree of reliability with respect to their predictive power of prognosis. It is therefore necessary to apply validated geriatric scores and specific scores of the patient for known morbidities in order to achieve the most complete vision possible before the diagnosis, in order to guide the treatment and its intensity [21].
\nIn addition to this, we must define what prognostic factors for relapse should be applied to these patients after treatment is initiated. Although several of them already known with importance in young group can also be applied to elderly patients, it should be determined which are more specific for this last group [26].
\nOne-quarter of all adults have Philadelphia chromosome, and the incidence increases with age. Until the results of recent studies in older patients became available, most patients with Philadelphia ALL were managed with intensive chemotherapy and a tyrosine kinase inhibitor (TKI). Imatinib has improved the CR rate in a number of trials to 90% and makes more patients eligible for transplant. Imatinib-resistant mutations are increasingly reported, and these should be sought in relapsed and refractory patients. Dasatinib, which inhibits tyrosine and src kinases, holds considerable promise. It may also be effective in CNS disease. There are no randomized comparisons with imatinib, although it is a more potent inhibitor of tyrosine kinase in vitro. Recent studies from Italy and France with dasatinib alone in older patients have achieved very high remission rates with encouraging short-term survival. Good minimal residual disease (MRD) responses correlated with outcome. Data regarding the combination of dasatinib and intensive chemotherapy are lacking. It is possible that less conventional induction therapy may be required and that allogeneic stem cell transplantation (SCT) may not be mandatory. The remarkable effectiveness of TKI therapy, in some studies without chemotherapy or allografting, has made us consider de-escalation of therapy, but the long-term results of these less intensive approaches are unknown, and allografting is the only known cure. The effect of pretransplant MRD status on outcome is unclear [27, 28].
\nA study of 267 patients (prior to the TKI era) showed allogeneic transplant to be superior to chemotherapy, with 44 and 36% surviving 5 years after sibling and unrelated donor SCT, respectively. However, only 28% of patients proceeded to a CR1 allograft, reducing its impact, and making it important that we improve no transplant therapy (and improve access to transplant). The Minneapolis group reported 50% survival in 14 patients who received reduced-intensity conditioning (RIC) allografts from cord or sibling donors. TKIs were used only for morphologic or molecular relapse posttransplant. Studies of TKI posttransplant that examine dose, duration, and molecular response are urgently required; this is the subject of studies from the German and UK groups that are soon to be reported [28, 29].
\nThe goal of remission induction therapy is to achieve remission without undue toxicity with a hematologic recovery that permits further therapy to be promptly given. Most regimens use prednisolone or dexamethasone, vincristine, daunorubicin, and asparaginase, with later exposure to cyclophosphamide and Ara-C (cytosine arabinoside or cytarabine). Hyper-cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD), which does not contain L-asparaginase, achieves high complete remission (CR) rates in newly diagnosed patients and is a reasonable alternative for induction therapy, but has not been shown to be superior to more traditional induction protocols. Dexamethasone is preferred to prednisolone because of superior lymphocytotoxicity, better central nervous system (CNS) penetration, and fewer thromboembolic events; these data are derived from pediatric studies. Poly(ethylene glycol)-asparaginase may be associated with more effective asparagine depletion, and this in turn may lead to better outcomes. But this requires a randomized comparison. The safety and optimum dose of this drug require further study in adults [25, 26, 30].
\nPopulation-based study registries give an impression on the overall outcome of unselected older ALL patients. Survival rates in patients aged 60 years were 12% at 5 years in Northern England. For those aged between 65 and 74 years, survival was 25% in Sweden where outcome further decreased to 10% in patients aged 74 years. Five-year OS in patients aged 60–69 years increased from 8% in the years 1992–2001 to 20% in the years 2002–2011, whereas only marginal improvements from 5 to 10% were observed for patients aged 70 years. Palliative treatment: some 30–70% of the older patients are allocated to palliative therapy mainly due to poor performance status at diagnosis. Most studies have shown an advantage of more intensive therapy such as higher CR rate, lower early death, better remission duration, and median survival compared with palliative treatment according to protocols for adult ALL patients. The majority of published data are based on results reported for the subgroup of older patients treated within protocols designed for adult ALL in general. One large data set confirmed considerable mortality of 18%. The conclusion that induction therapy designed for younger patients may be too intensive for older patients. Patients may acquire severe infections, nonpredefined treatment modifications occur frequently, and treatments may be interrupted or even stopped due to severe complications. Overall, potential conclusions from these studies are very limited. Prospective studies of protocols for older ALL patients specifically designed for older ALL patients have the theoretical aim to provide a chance of cure on the one hand and to limit toxicity, early mortality, and hospitalization duration on the other hand, and the therapy maintains as much quality of life as possible. One central question is whether and/or which anthracycline has to be included in induction regimens for older patients, because these drugs contribute considerably to bone marrow toxicity [5, 6, 15, 31]. One approach is the use of idarubicin in induction, based on a potentially lower cardiac and hepatic toxicity. The results of liposomal anthracyclines in elderly ALL are not convincing so far. Asparaginase is an essential compound in the treatment of ALL. The PETHEMA group reported the results of an intensive induction regimen, including asparaginase for older ALL patients. The early death rate, mainly due to infection, was rather high (36%) and was reduced after omission of asparaginase and cyclophosphamide. A high early mortality rate (29%) and a number of complications including infections (71%), cardiac toxicity (18%), and hyperglycemia (24%) were also observed in another trial utilizing asparaginase during induction therapy. Furthermore, a pediatric-based regimen using pegylated asparaginase during induction in older patients revealed grade 3–4 bilirubin increases in 33% of the patients. Thrombosis and pancreatitis are other relevant toxicities of asparaginase. Altogether, there is some evidence that the use of asparaginase during induction therapy may be associated with increased risks in older patients. Therefore, it would be advisable to start asparaginase in older patients later during consolidation. The majority of complications in older ALL patients is observed during induction; thus, there is still space for intensification of consolidation therapy [14, 23, 32]. Based on this assumption, a consensus treatment protocol for older patients with ALL was defined by the European Working Group for Adult ALL (EWALL). The 4-week, pediatric-based induction comprises dexamethasone, vincristine, and idarubicin in phase 1 and cyclophosphamide and cytarabine in phase 2. Consolidation consists of six alternating cycles with intermediate-dose methotrexate combined with asparaginase and high-dose cytarabine, followed by maintenance. The median age at enrollment was 66 (56–73) years with 22% at 70 years. The incidence of grade 3–4 cytopenias was 90%, and infections during phases 1 and 2 of induction occurred in 16 and 25% of the patients, respectively. Toxicities were less pronounced during consolidation, and asparaginase was well tolerated. CR, survival, and continuous CR rates after 1 year were 85, 61, and 49%, respectively. Another report based on the same backbone showed CR rates of 74% and an OS of 30% at 2 years [18, 20, 33]. The authors also observed grade 3–4 infections in 62% of the patients during induction therapy with a median duration of neutropenia of 24 days, whereas consolidation was far better tolerated even when including the use of asparaginase [18, 20, 23, 34]. The GMALL has conducted thus far the largest prospective trial specifically designed for older patients with Ph/BCR–ABL-negative ALL. Pediatric (Berlin-Frankfurt Munster)-based, dose-reduced induction therapy with idarubicin, dexamethasone, vincristine, cyclophosphamide, and cytarabine was followed by alternating consolidation cycles for 1 year and maintenance. Patients with CD201 ALL received rituximab in combination with chemotherapy. The median age of this cohort was 67 (55–85) years. In 268 patients, the CR rate was 76%, early death rate 14%, mortality in CR 6%, continuous remission 32%, and survival 23% at 5 years. Patients aged 75 years with an Eastern Cooperative Oncology Group performance status below 2 had an 86% CR rate, 10% early death, and 36% survival at 3 years. Interestingly, the replacement of triple intrathecal therapy during induction resulted in a reduced early mortality. Moderate intensification of consolidation as in the EWALL regimen, with inclusion of high-dose cytarabine and intermediate-dose methotrexate and native Escherichia coli asparaginase was tolerated [24, 26, 30].
\nOverall, mortality in CR was 6% only. Overall, pediatric-based regimens in ALL are undoubtedly successful and should be scheduled with prospectively defined adaptations with respect to tolerability in older patients. The most important modification of induction therapy in older patients is probably the omission of asparaginase, and the flexible, reduced dose of anthracyclines. In consolidation, intensified treatment should be attempted, and during this treatment phase, even asparaginase may be surprisingly well tolerated at moderate doses [29, 34]. In this treatment, patients aged 55–70 years and 70–75 years tolerated pegylated asparaginase at dose levels of 1000 and 500 U/m2, respectively, as single-drug interim therapy during consolidation. Combination with high-dose methotrexate will be further explored and careful use is recommended in patients with preexisting liver disease. [23, 24, 26, 30, 35]. Nowadays, older patients with Ph+ ALL may have a better chance to achieve a CR than patients with Ph+ ALL. The use of TKIs upfront is most promising. The GMALL conducted a first randomized study to evaluate the efficacy of imatinib single-drug induction compared with chemotherapy. The remission rates were 96 and 50%, respectively. Only 11% of the patients achieved a molecular remission. A follow-up including nonrandomized data yielded a CR rate of 88% in 121 patients, together with a 22% 5-year survival rate. The Gruppo Italiano Malattie Ematologiche dell’Adulto trial used imatinib (800 mg) with prednisone for induction, followed by imatinib single-drug treatment. The CR rate, survival, and disease-free survival were 100, 74, and 48%, respectively, after 1 year. A subsequent trial with dasatinib (140 mg) and prednisone, followed by dasatinib single-drug treatment, was not specifically designed for older patients (range, 24–76 years). The CR rate was 92% and survival was 69% at 20 months. Postremission therapy was at the discretion of the treating physician and 14 of 19 patients with TKI monotherapy relapsed with a high frequency of T315I mutations [31, 33, 35]. Another trial was based on a rotating schedule with 6 weeks of nilotinib treatment alternating with imatinib treatment. In 39 patients, the CR rate was 94% and the OS at 1 year was 79%. Nearly, all relapsed patients in this trial showed mutations associated with TKI resistance. The largest prospective study so far in older patients with Ph+ ALL used an EWALL chemotherapy backbone with vincristine, dexamethasone, and dasatinib (140 mg) for induction. Consolidation and maintenance according to the EWALL backbone was combined with intermittent dasatinib applications. In 71 patients, the CR rate was 96%. The regimen was feasible and the survival after 5 years of follow-up was 36%, which is promising. Persistent MRD above 0.1% after induction and consolidation was associated with poorer remission duration of only 5 months. A subsequent EWALL trial with a similar backbone but with nilotinib (400 mg twice daily) instead of dasatinib was started subsequently. Again, a high CR rate of 97% was reported. About 30% of patients achieved a complete molecular remission after induction. Overall, there is increasing evidence that second-generation TKIs in combination with dose-reduced chemotherapy can induce very high CR rates with low mortality in older patients. The rate of molecular remissions appears to be higher compared with imatinib-based regimens. Moderate intensive consolidation therapies in combination with TKIs are tolerated well. Long-term results have to be assessed after 5 or more years and show a still high rate of relapses. New approaches may include reduced intensity stem cell transplantation (SCT), MRD-based change of TKIs, or use of new immunotherapies [23, 36, 37].
\nIn other study, 127 patients with ALL were enrolled including 26 elderly patients (≥60 years) and 101 younger adult patients (<60 years). The median follow-up durations were 6.0 months (range, 0.4–113.2) in the elderly patients and 21.7 months (range, 1.0–122.7) in the younger patients. The median age of the younger patients with ALL was 30 years (range, 15–58), whereas that of the elderly patients with ALL was 65 years (range, 60–82). No significant differences in the baseline characteristics of the two groups were observed, except in history of malignancy; a larger portion of elderly patients with ALL had a history of malignancy (p = 0.001). The composition of ALL subtypes and the frequencies of Ph+ status were not statistically significant between the two groups. The peripheral blood sample laboratory findings showed more severe anemia in younger adult patients with ALL than in the elderly patients (p = 0.023); of 26 elderly patients with ALL, abnormal karyotypes were found in 14 patients (53.8%) [38, 39].
\nAll patients, with the exception of two elderly patients who received supportive care only, received induction chemotherapy. About half of the elderly patients (12 patients, 46.2%) received the VPDL regimen as an induction therapy. Five elderly patients (19.2%) were administered the VPD regimen, and one (3.8%) was administered the hyper-CVAD (cyclophosphamide 300 mg/m2, D1–3; vincristine 2 mg D4,11; Adriamycin 50 mg/m2, D4; dexamethasone 40 mg D1–4, D11–14) regimen. The overall CR rate was much higher in the younger adult patients than that in the elderly patients (94.1 vs. 57.7%, p < 0.001). Early mortality within 3 months from the start of induction chemotherapy was remarkably higher in the elderly patients (26.9% vs. 5.0%, p = 0.003).
\nThe median number of postremission consolidation therapy sessions was three (range, 1–5) in the elderly patients with ALL. The regimen in the elderly patients was vincristine and prednisolone in seven patients. Two patients received only imatinib due to severe comorbidities. One patient received the CALGB 9251 regimen, and the other patient received nonmyeloablative hematopoietic stem cell transplantation (HSCT) from a matched sibling donor. Of 15 elderly patients who achieved CR, only 11 received postremission therapy. The overall nondisease-related mortality rate in the elderly patients was higher than that in the younger adult patients.
\n\n
Cumulative hazards of disease-related and nondisease-related mortality in younger adult patients (<60 years) with acute lymphoblastic leukemia (ALL) and in elderly patients (≥60 years) with ALL (p = 0.001 and 0.12, respectively).
\nThe median OS of the younger patients was 26.3 months (95% confidence interval [CI], 19.6–33.0), whereas that of the elderly patients was 10.3 months (95% CI, 3.5–17.2) (p = 0.003). The survival difference according to age was not reproduced in the subpopulation of patients with Ph-positive ALL (data not shown), but was consistently found in the patients with Ph-negative ALL.
\n\n
Overall survival (OS) of elderly and younger adult patients with acute lymphoblastic leukemia (ALL): OS of elderly patients with ALL (≥60 year) was shorter than that of younger adult patients with ALL (<60 year) (median OS 10.3 vs. 26.3 months, respectively, p = 0.003).
OS of the elderly and younger adult patients with Philadelphia chromosome (Ph)-negative ALL: OS of the elderly patients with Ph-negative ALL (≥60 year) was shorter than that of adult patients with Ph-negative ALL (<60 year) (median OS, 10.3 vs. 29.2 months, respectively, p = 0.01).
OS according to complete remission in elderly patients with ALL: OS of elderly patients with complete remission was longer than that of elderly patients without complete remission (median OS, 13.1 vs. 2.6 months, p = 0.001).
OS according to age (60–69 vs. ≥70 years) in elderly patients with ALL: OS of elderly patients aged 70 years or more was not significantly different from that of the other elderly patients (median OS, 11.2 vs. 3.7 months, p = 0.073) [40, 41].
Among the elderly patients, the patients who achieved CR1 (CR after the first induction chemotherapy) showed significantly longer survival compared with those who did not achieve CR1 (median OS, 13.1 vs. 2.6 months; p = 0.001). Furthermore, CR1 was the only independent prognostic factor for OS in elderly patients with ALL (p = 0.001). Although the OS of elderly patients aged 60–69 tended to be longer than that of those aged 70 or over, the difference did not reach statistical significance (median OS, 11.2 vs. 3.7 months; p = 0.073).
\nIn the survival analysis using the factors at the initial ALL diagnosis, the probable poor prognostic factors for CR were age ≥ 70 years (relative rate of remission [RR], 0.14; 95% CI, 0.013–1.45; p = 0.098) and leukocytosis (≥30,000/μL) (RR, 6.00; 95% CI, 0.93–38.63; p = 0.059). T-cell lineage and the presence of lymphadenopathy were significant factors in poor prognosis for OS in the univariate analysis (hazard ratio [HR], 3.11 and 3.14; 95% CI, 1.14–9.34, and 1.01–9.99; p = 0.033 and 0.041, respectively). T-cell lineage and Ph-positive status tended to increase the HR for leukemia free survival (LFS) (HR, 8.49 and 4.49; 95% CI, 0.53–135.82 and 0.8–25.21; p = 0.069 and 0.064, respectively).
\nUnivariate analysis for complete remission, overall survival, and leukemia-free survival in elderly patients with ALL (≥60 year) (n = 26).
\n\n
ALL, acute lymphoblastic leukemia; RR, relative rate of remission; CI, confidence interval; HR, hazard ratio; Ph, Philadelphia chromosome; WBC, white blood cell.
\nThe low response to chemotherapy in the elderly patients with ALL could be related to several factors. The first factor may be chemotherapy intensity. Intensified combination induction chemotherapy can result in an improvement in the CR proportion, and high-dose postremission methotrexate (MTX) or cytarabine therapy is effective for treating adult ALL. However, most elderly patients with ALL in our study could not receive the postremission therapy after the induction therapy with a standard or reduced dose and also could not be treated with intensified postremission regimens such as cyclophosphamide or MTX, though they received postremission therapy. The second factor may be drug-resistance mechanisms such as the presence of multidrug-resistance gene 1 and multidrug-resistance-related protein.
\nAlthough intensified induction chemotherapy was not introduced, and postremission therapy was not performed appropriately in most elderly patients with ALL, the survival benefit was definite in the patients who achieved CR. Our study did not show a statistical difference in nondisease-related mortality rates between the elderly and younger adult groups. However, the actual risk of nondisease-related mortality might be significantly higher in the elderly patients considering that only a few patients could receive highly toxic therapy such as HSCT, and our results indicated that about half (43.8%) of nondisease-related mortality was related to HSCT in the younger adult patients with ALL [40, 41, 42, 43].
\nALL blasts express a number of antigens, such as CD33, CD22, CD19, and CD52, which could be targets for antibody therapy. The majority of older patients suffer from B-precursor ALL. In this subtype, approximately half of the patients show CD20 expression on their blast cells. In younger patients with CD20+ ALL, the first promising data for the combination of chemotherapy and rituximab have been reported. Outcome of older patients could be hampered by a higher mortality due to infections in CR, which underlines the need for intensive supportive care for older patients throughout the entire treatment period.
\nA great majority of cases with ALL in elderly patient correspond to B-precursor lineage, one of the characteristics of this lineage is the expression of CD20 on its surface, which makes it susceptible to treatments focused on this marker, such as rituximab, this treatment approach has already shown to be highly effective in young patients, which could be transposed to the population over 65 years of age.
\nA promising new approach is the administration of a bispecific CD19 antibody, blinatumomab, which has the potential to engage cytotoxic T cells in patients for lysis of CD19+ leukemia cells. In 19 patients with refractory disease, defined as hematologic remission with persistent MRD after intensive chemotherapy, the molecular remission rate was 84%. A number of older patients who were not able to receive an SCT remained in remission for more than 1 year. More recently, a CR rate of 68% was reported for relapsed ALL. All patients with CR also achieved a molecular CR. Treatment with the final dosing regimen was well tolerated, and a number of older patients experienced a benefit. The CD22 directed, calicheamicin-conjugated antibody inotuzumab induced 18% CRs and 39% marrow CRs in relapsed CD22+ ALL. Toxicity appeared to be manageable, and the mortality of 4% within 4 weeks was moderate. Successful future use of antibody treatment will certainly depend on well-designed combination regimens with chemotherapy that aim to achieve long-term responses, particularly in older ALL patients.
\nIn recent years, there have been advances and new therapeutic options in the management of ALL, one of the most promising is immunotherapy, specifically bispecific antibodies, the first of which useful information was disclosed was blinatumomab, this antibody that acts by binding to T lymphocytes, activating them and forcing them to destroy CD19 receptor expressing cells, such as blasts, already has multiple studies in various population groups that demonstrate their effectiveness against the disease, achieving significant response rates (84%) and negativization of the MRD. Another new specific antibody against the CD22 receptor, inotuzumab, has also been shown to be effective, at least in its initial studies, with a tolerable safety profile. The great advantage of these new treatments is that they do not confer the implicit risk in chemotherapy; however, there are no studies specifically in elderly patients.
\nSeveral other new drugs are of interest for optimizing treatment in older ALL patients. Although the number of older patients with T-ALL is low, the use of nelarabine is of interest after promising results and acceptable toxicity in relapsed T-ALL including older patients. Liposomal cytarabine for intrathecal application showed activity and tolerability in CNS relapse of ALL, although in combination with systemic neurotoxic regimens, severe toxicities may be observed. The use of liposomal cytarabine in prophylaxis of CNS relapse is of interest, particularly in older patients, since it allows reduction of the number of intrathecal injections and may induce fewer systemic toxicities compared to conventional intrathecal therapy.
\nOther drugs of current interest include nelarabine, indicated for use in cases of T-ALL. The prophylactic treatment to CNS has also had new protagonists in its field, liposomal cytarabine is one of these; this drug used for both prophylaxis and management of relapse to CNS has shown to be safe, although when combined with other neurotoxic agents, there is considerable toxicity. Despite this, safety is comparable to that presented by conventional cytarabine, with a higher rate of effectiveness.
\nLiposomal vincristine is another drug of interest, particularly in older patients. Results are still pending on the major question of whether liposomal encapsulation allows a higher dose intensity with lower risk of neurotoxicity. Bendamustine could be of interest, since it has shown limited toxicity and favorable results in older patients with B-cell lymphoma. New drugs with different mechanisms of action may, in the future, be used in combination with chemotherapy, such as proteasome inhibitors, histone-deacetylase inhibitors, hypomethylating agents, or targeted drugs such as Flt3 inhibitors or Jak2-inhibitors in defined subgroups of ALL. Currently, these compounds are either available in clinical trials or could be considered in individual patients with poor response to standard chemotherapy, including patients with molecular failure [12, 23, 43, 44].
\nBendamustine and liposomal vincristine are new tools already known, the first one, a drug developed in the 1960s, has shown its effectiveness in various studies in the management of ALL and other lymphoproliferative disorders, with adequate safety in elderly patients. New mechanisms of action must be explored in order to give variety to the maneuvers against the disease. The study of new prognostic and risk markers that can be targeted by these drugs is crucial for their development. Currently, a large number of studies are underway in the world, both with new combinations of already known drugs and with novel molecules applicable to ALL [12, 23, 43, 44].
\nAll older ALL patients need a comprehensive diagnostic classification, including, at least, immunophenotyping, molecular diagnostics, and setup of an assay for MRD evaluation. The identification of Ph+ ALL is crucial since, even in very old and frail patients, TKIs induce a high CR rate with reasonable durability. Furthermore, the biological characterization of older ALL patients needs to be improved. Biobanking for future scientific investigations within clinical trials should therefore be standard in older as it is in younger patients.
\nAltogether, in older as in younger patients, a pediatric-based induction strategy is recommendable in Ph− ALL. Dose reductions for anthracyclines are essential, and asparaginase during induction cannot be recommended outside of clinical trials. Dexamethasone appears to increase efficacy in younger patients, but prolonged use should be avoided. For fit older patients, consolidation chemotherapy may be intensified. Moderate-dose consolidation, including methotrexate, cytarabine, and reinduction therapy, appears to be feasible, and maintenance treatment is an essential treatment element.
\nIn unfit older patients, a dose-reduced induction therapy is recommended with the aim of controlling and achieving a prolonged low-level disease. ALL-specific approaches should be considered, including vincristine, steroids, intrathecal therapy, and maintenance with mercaptopurine and methotrexate. Many physicians have more experience with older AML patients; however, there is no rationale for using AML regimens such as low-dose cytarabine or hydroxyurea in ALL.
\nWhen they are available, targeted drugs such as nelarabine, monoclonal antibodies, or other new drugs with potentially reduced or alternative toxicity should be added to treatment strategies in older patients, preferably in clinical trials. Since many of these compounds are used off-label, it may be useful to make the indication based on persistent MRD, which, in addition, offers a chance to evaluate effects immediately. Treatment options may change as soon as new drugs or strategies become available. With effective drugs for prolonged maintenance, it may be possible to further reduce intensity of induction therapy and avoid early mortality in unfit patients.
\nIn Ph+ ALL, it is still not clear whether further reduced induction chemotherapy adds an effect to TKI therapy and which inhibitor is preferable. I favor a combination therapy. Moderate dose consolidation and maintenance should be offered. Patients should be considered as candidates for RIC SCT.
\nWhereas full-conditioning regimens before SCT are clearly not recommended, RIC SCT is an option in older patients. For indication, it will be crucial to define prognostic factors. Because persistence of MRD is one of the most important risk factors, MRD evaluation should take place in older patients to identify those who could benefit from experimental therapies or SCT. This also applies to Ph+ ALL regarding the option of changing the TKI.
\nThere are a number of neurological disorders that fall under the umbrella of neurodegeneration, with the major ones including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), spinal cord injury (SCI), and others. Currently, there are no generally effective treatments available to slow down or reverse the debilitating effects of these diseases, and the long-term effects of these diseases are the progressive degeneration and death of neurons. A majority of the neurodegenerative diseases are linked with inflammation in CNS [1], and the presence of activated glial cells, infiltration and activation of adaptive and innate immune cells, increased presence of inflammatory molecules such as cytokines and chemokines, and increased oxidative stress and reactive oxygen species (ROS) are the main neuroinflammatory characteristics present in lesions associated with these neurodegenerative disorders. Recent approaches found to be effective in the treatment of Parkinson’s disease involve the use of anti-inflammatory agents and cytokines such as agonists to the β2-adrenergic receptors (β2-AR) to inhibit neuroinflammation and the progression of dopaminergic neurodegeneration. In this chapter, we will address the current understanding of therapeutic approaches targeting neuroinflammation linked with PD and the use of β2-AR agonists as an effective treatment for PD.
\nParkinson’s disease (PD) is a progressive neurodegenerative disorder which leads to impaired motor skills. The major pathological feature of PD is the degeneration of dopaminergic (DA) neurons which project from substantia nigra (SN) to the striatum in the midbrain (nigro-striatal pathway) [2]. Another neuropathological feature of PD is the cytoplasmic inclusion of misfolded α-synuclein protein in degenerating dopaminergic neurons called Lewy bodies [3]. The primary motor symptoms of PD, such as tremor, rigidity, and bradykinesia, are caused by inadequate formation and neurotransmission of dopamine within the nigro-striatal pathway [4, 5]. Dementia is reported in 28% of PD cases with the prevalence rising to 65% in those aged 85 years and above. Patients with PD also show non-motor-related symptoms such as olfactory deficits, depression, cognitive deficits, sleep disorders, and autonomic dysfunction [6]. The majority of PD cases are idiopathic Parkinson’s, and the disease mechanism that ultimately causes idiopathic PD is largely unknown. In the remainder of the cases of PD, about 10–15% of patients do have a family history and those patients are referred to as having the familial form of PD. For these patients, their PD appears to be caused by a mutation in one of a few selected genes (such as SNCA, Parkin, LRRK2, DJ-1, etc.) [7, 8]. Although the etiology of the idiopathic form of the disease remains elusive, there are some risk factors associated with the development of the disease. These risk factors include exposure to environmental toxins, severe cranial trauma, systemic or localized infections, and inherited genetic risk factors. These genetic and nongenetic risk factors have the potential to initiate neurodegeneration and subsequent chronic inflammation in the brain which eventually contributes to the pathophysiology of PD [9]. In addition, several cellular and molecular pathways such as oxidative stress [10], proteosomal dysfunction [11], excitotoxicity [12], and mitochondrial dysfunction [13] have also been identified which contributes to neuronal death.
\nThe presence of activated glial cells, increased inflammatory molecules such as cytokines/chemokines, and increased oxidative stress and ROS are the main neuroinflammatory characteristics present in PD [14]. PD is now not only characterized as loss of DA-neurons and motor impairment, but also recognized to have an inflammatory component which plays a crucial role in the progression of the disease. Several inflammatory mediators such as TNF-α, IL-1β, ROS, and nitric oxide (NO), released from nonneuronal cells exacerbate the disease pathology [3, 15]. It has been suggested that α-synuclein released from dying neurons also activate the microglia via TLR2 activation [16]. Furthermore, the elevated levels of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 have been reported in serum, cerebrospinal fluid (CSF), and striatum of PD patients [17]. The influx of peripheral macrophages has been reported in brains of patients with PD, but the role of these cells in disease pathology remains to be tested [18]. Additionally, activation and increased number of glial cells and infiltrating peripheral lymphocytes such as cytotoxic CD4+ and CD8+ cells in SN also support the role of adaptive immunity in the etiology of the disease [8]. Overall, these studies and others suggest the contribution of the immune system in the pathophysiology of PD.
\nMicroglia originate from erythromyeloid progenitors in the yolk sac which migrate and differentiate during development to form the central nervous system (CNS). Fully differentiated microglial cells are also considered to be the resident macrophages of the CNS [19], although some phenotypic and functional differences between microglia and macrophages have been found [20]. Growing evidence suggests that the activation of microglia in CNS plays an important role in the pathogenesis of PD. It is not well understood how microglia activation is either beneficial or detrimental to the neuron or how microglial activity is regulated. It has been found that microglial activation is required for neuronal survival by the removal of toxic substances through innate immunity [21]. On the other hand, it has been found that over-activated microglial cells are detrimental and neurotoxic [22]. Research studies of post-mortem brain tissue from patients with PD and related parkinsonian syndromes suggest the presence of activated microglia around degenerating DA-neurons in the SN [23] and these activated microglia are not only limited to the SN but also present in extended brain areas such as hippocampus, putamen, trans-entorhinal cortex, cingulate cortex, and temporal cortex [24]. Imaging of activated microglia in the striatum could be used as a biomarker for detecting neuroinflammation in neurodegenerative parkinsonian disorders [25]. The resting microglia switches to an activated microglia phenotype in response to pathogen invasion or release of toxic or inflammatory mediators and thereby promotes an inflammatory response [1]. Once activated, microglial cells produce a wide range of inflammatory mediators which serve to initiate an innate immune response or glial cell-propagated inflammation termed as neuroinflammation [26]. Also, the degenerating DA-neurons release many toxic factors that activate microglia and these degenerating neurons are vulnerable to inflammatory insult. Degenerating neurons will co-localize or attract an even larger population of microglia in the SN [27]. Collectively, these activated microglia and damaged neurons form a repetitive and vicious cycle that leads to chronic inflammation and continued extensive DA neurodegeneration over time, leading to the progression of PD [27]. These findings confirm neuroinflammation as a pivotal process in the progression of neurodegenerative disorders and the central role of microglia in this process [22]. Targeting neuroinflammatory pathways within microglia could be a significant step in the development of new therapeutics for neurodegenerative diseases, including PD.
\nTreatment for PD normally involves medications such as Levodopa to enhance the dopamine levels and deal with movement symptoms [28]. While none of our current treatments are able to stop the disease, medication and surgery can be helpful for managing the symptoms [29]. These treatments work well in patients initially, but they are also associated with unwanted side-effects and reduced efficacy over time [30]. On the other hand, many studies suggest that inflammatory mediators such as TNF, PGE2, NO, free radicals, and other immune mediators play role in the pathogenesis of PD and degeneration of dopamine-producing neurons and that targeting these mediators can be an effective treatment for PD. This opens up the potential of using anti-inflammatory drugs as an effective and long-term treatment in PD. These anti-inflammatory drugs can act by arresting the disease onset (primary prevention) or by interrupting or even reversing the disease progression (secondary prevention). Epidemiological and observational studies suggest that the use of anti-inflammatory drugs lower the risk of developing PD [31]. Observations which demonstrated that inflammation in SN plays a role in PD have led many investigators to initially consider the potential use of both steroidal and nonsteroidal anti-inflammatory drugs for the treatment of PD. Steroidal anti-inflammatory drugs (SAIDs), such as dexamethasone, have shown neuroprotective effects in LPS-induced neurotoxicity in the SN in LPS models of PD [32]. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been used as analgesics and antipyretics to suppress the adverse effects of inflammation [33]. The neuroprotective effects of Ibuprofen have been studied in PD pathogenesis and these studies demonstrate the protective effect on dopaminergic neurons against glutamate toxicity in vitro [34, 35]. Previously, we have established several therapies targeting neuroinflammation and neurodegeneration in an animal model of PD and these therapies include D-morphinan-related compounds [36], anti-inflammatory cytokines such as TGF-β (transforming growth factor-beta) [37] and IL-10 [38, 39], IKK (inhibitor of kappa B (IκB) kinase) inhibitors [40], NADPH (nicotinamide adenine dinucleotide phosphate) oxidase inhibitors [41], and β2-AR (beta 2-adrenergic receptor) agonists [42, 43].
\nWe have conducted a number of experiments using different classes of anti-inflammatory compounds to determine their efficacy in preventing dopaminergic neurotoxicity by activated microglial cells both in vitro and in vivo. First, it was found that morphinan compounds and their stereoisomers (L-morphine and its D stereo enantiomers) can inhibit microglial activation and LPS- or MPP+-induced neurotoxicity in rat primary mesencephalic cultures. We and others observed that several dextrorotatory isomers of morphine compounds, including D-morphine, dextromethorphan, and sinomenine, showed neuroprotective effects against LPS and MPP+ (1-methyl-4-phenylpyridinium) which were mediated through the inhibition of microglial PHOX activity [36, 44, 45]. Furthermore, these studies also suggest that these morphinan compounds bind to the catalytic subunit of PHOX, inhibit its activity, and reduce the production of superoxide and other pro-inflammatory cytokines [44]. In another set of studies using a different anti-inflammatory approach, a specific inhibitor of IKK-β (IkappaB kinase-beta) protects dopaminergic neurons against LPS-induced neurotoxicity both in vitro and in vivo through inhibition of NF-κB activation, resulting in the decreased production of ROS and inflammatory cytokines [40]. We have also developed therapies targeting neuroinflammation in PD models by using anti-inflammatory cytokines such as IL-10 and TGF-β1, and found that treatment with IL-10 on rat mesencephalic neuron-glia culture protects against LPS-induced neurotoxicity via suppression of pro-inflammatory mediators and superoxide production [38]. Similarly, the neuroprotective effect of TGFβ1 is primarily due to its ability to inhibit ERK phosphorylation, the serine phosphorylation on p47\nphox\n, and the production of ROS from microglia during activation by LPS [37].
\nOne of the most potent and successful therapeutic treatments for inflammation-mediated dopaminergic neurotoxicity is the use of long-acting agonists to the β2-AR. Adrenergic receptors (AR) are seven-transmembrane proteins that serve as adrenoreceptors for catecholamines such as norepinephrine and epinephrine on multiple cell types, and cells within the CNS that express AR include neurons, immune cells, and astrocytes. Pharmacological classification of the adrenergic receptor was first introduced in 1948 and broadly classified as α and β adrenergic receptors [46] by Ahlquist. The classification was based on the order of potency and specificity of natural and synthetic agonist and blocking agents. The α-AR response corresponds to mainly excitatory response, while β-AR responses were correlated mainly with the inhibitory response. The α-AR response showed the order of potency: norepinephrine > epinephrine > isoproterenol and β-AR-mediated response exhibited order of potency: isoproterenol > epinephrine > norepinephrine [47, 48]. After the discovery of new drugs which have a high affinity to adrenergic receptors, these receptors were sub-classified. α-AR were subdivided into α1 and α2 adrenergic receptors [49]. Further studies subdivided β-AR into β1 and β2 which are normally present on immune cells, cardiac muscles, and airway smooth muscles, respectively [50]. A third β-AR, now called as β3-AR was identified on adipose tissues [51]. Tissue distribution, physiological effects, mechanism of action, and the major agonists/antagonists of ARs are summarized in \nTable 1\n. Pharmacological compounds that serve as short, long, and ultra-long-acting agonists for these receptors have now been developed, and they are normally thought to stimulate adrenergic receptors by four different mechanisms: (1) by direct receptor binding, the most common mechanism where drugs activate peripheral adrenergic receptors via direct binding to receptor and mimic the actions of endogenous agonists (NE, epinephrine), (2) by ameliorating NE release, where drugs act on sympathetic nerve terminals and results into NE release, (3) by inhibition of NE reuptake, where these drugs can cause NE to accumulate within synaptic gaps at sympathetic nerve terminals, (4) by blockade of NE inactivation where drugs inhibit the activity of monoamine oxidase (MAO) which inhibits the activity of monoamines such as NE and dopamine [52].
\nCharacteristics of adrenergic receptors.
The β2-ARs belong to a diverse superfamily of human cell surface seven transmembrane receptors for hormones and neurotransmitters called G-protein-coupled receptors (GPCRs). GPCRs are divided into six classes on basis of sequence homology: class A (Rhodopsin-like), class B (Secretin receptor family), class C (Metabotropic glutamate), class D (Fungal mating pheromone receptor), class E (Cyclic AMP receptor), and class F (Frizzled/smoothened) [53]. GPCRs are one of the most extensively studied proteins for the development of pharmaceutical drugs and target for approximately 50% of the marketed pharmaceutical drugs [54]. The adrenergic receptor family belongs to the rhodopsin-like subfamily, the largest class of the GPCR. The β2-AR is an intron-less gene is present on the long arm of chromosome 5 (5q31) and encodes for 413 amino acid polypeptide of 46kD [55]. Similar to all GPCRs, β2-AR is composed of seven transmembrane spanning α-helices with an intracellular C-terminus and an extracellular N-terminus. The β2-AR was the first GPCR to be cloned [56] and the first GPCR structure to be solved [57]. The β2-AR has been studied extensively and also serves as a model system for investigating the regulation and signal transduction of GPCRs. The study of the 3D protein structure of this family of GPCRs took a giant leap forward when rhodopsin was first crystallized in 2000 and this crystalline structure has been used as an important template for modeling other GPCRs in this family [58]. The crystalline structure of human β2-AR was not solved until 2007, when a nonactive structure of β2-AR was identified [57]. Post-translational modifications such as glycosylation, pamitoylation, disulfide bond formation, and phosphorylation have now been found to affect receptor functions. Interestingly, β2-AR is glycosylated at amino acid 6, 15, and 187 which is important for the trafficking of the β2-AR from the endoplasmic reticulum to the plasma membrane [59]. Mutation in these sites also results in reduced expression of receptor on the cell membrane, suggesting a role for glycosylation in cell surface expression [60]. Conversely, the cysteine amino acid in the cytoplasmic tail at position 341 is palmitoylated, and is now found to be an important residue for the adequate coupling of the receptor to the Gs-protein [61]. Finally, β2-ARs have disulfide bonds which are essential for agonist binding and also for maintaining their tertiary structure [62].
\nAdrenergic receptors are widely distributed on human body organs and regulate physiologic functions such as bronchodilation [63], vasodilation, glycogenolysis in the liver, and relaxation of uterine and bladder muscles [64]. The human β2-AR are widely expressed not only on airway smooth muscles, but also on the wide variety of cells such as epithelial cells, endothelial cells, brain cells, and immune cells including mast cells, macrophages, adaptive immune cells, and eosinophils [65]. The expressions of β1- and β2-AR have also been found on microglial cells, suggesting that microglia, the brain’s resident immune cell, is predominantly regulated by NE since NE is the predominant catecholamine in the CNS. Conversely, peripheral immune cells such as macrophages and T cells, which also express high levels of β1 and β-2 AR, are thought to be regulated primarily by epinephrine [66].
\nActivation of adrenergic receptors could result into both pro- and anti-inflammatory actions, depending on certain parameters such as the type of cell, duration of ligand exposure to the receptor, and type of the adrenergic receptor [67]. It is the diversity of the β2-AR that leads to the complexity of signaling mechanisms and to this duality of function. Activation of β2-AR by receptor agonists initiate intracellular signaling pathways that function either via G-proteins or through β-arrestins. Like other GPCR, β2-AR can activate either canonical (traditional) or noncanonical (nontraditional) signal transduction pathway. In the canonical pathway, similar to a typical GPCR the β2-AR signals via a heterotrimeric G-protein complex, and when the receptor is coupled to inactive GDP-bound G-protein, it appears to have high affinity to the agonist or ligand. After ligand binding, the transmembrane domains of the receptor undergo conformational change with the exchange of GDP to GTP. Further, this conformational change reduces the affinity of the ligand to its receptor, increasing the possibility of retraction of ligand from the receptor, thereby preventing the over-activation of G-protein. This provides evidence that β2-AR appear to oscillate between an active and inactive form under normal conditions. After the exchange of GDP to GTP, the Gα-subunit dissociates from Gβγ-subunit which remains associated with plasma membrane and the Gα-subunit activates effector proteins. The downstream signaling of this process normally results in the production of intracellular second messengers which further activates the cAMP-PKA-mediated intracellular signaling pathway. The activated β2-AR binds with the α-subunit of the G-protein together with a guanosine triphosphate (GTP) molecule. Further, the receptor coupled with adenylate cyclase (AC) which catalyzes the conversion of ATP into cAMP (a second messenger for β2-AR) by hydrolysis of GTP into GDP. The cAMP activates and regulates protein kinase A (PKA) which further mediates the transcription of genes and degradation of cAMP by phosphodiesterase (PDE) leading to termination of signaling [68].
\nEarlier it was determined that β2-AR exhibits their inhibitory signals in immune cells via the canonical (PKA) signaling pathway. It has now been found that GPCR can also signal through a noncanonical pathway in addition to their classical signaling pathway [69]. Activation through the noncanonical signaling pathway is cell type dependent and G-protein independent, but rather the G-protein-coupled receptor kinases (GRKs) and β-arrestins are involved in activation of this noncanonical signaling pathway. Various types of GRKs phosphorylate specifically serine and threonine at C-terminal of the β2-AR which further determines whether receptors undergo desensitization or initiate noncanonical signaling [70]. For example, phosphorylation of receptor by GRK5/6 initiates β-arrestin-mediated noncanonical signaling, while phosphorylation by GRK2 leads to β-arrestin-mediated desensitization of the receptor [71]. During noncanonical signaling, β-arrestin2 couples β2-AR to MAPK signaling pathways which induces activation of transcription factors and allows their nuclear translocation. Activation of β2-AR with high agonist concentration can lead to sustained activation of ERK1/2 via β-arrestin2. This explains why β2-AR activation can either enhance or suppress the proliferation of immune cells and cytokine production particularly at a high concentration of agonists [67, 72]. Studies suggest that during inflammatory conditions immune cells can switch from canonical to the noncanonical pathway [67, 68]. Engagement of β2-AR receptors by agonists can result in immunomodulatory actions. Depending on the type of immune stimuli and timing of β2-AR activation relative to immune activation, β2-AR stimulation can positively or negatively regulate the response of immune activator [67, 73]. The initial data obtained in animal models of dopaminergic neurotoxicity suggests that the primary immunomodulatory mechanism of β2-AR activation that regulates CNS inflammation in microglial cells occurs through the noncanonical β-arrestin2 pathway of activation.
\nβ-agonists are a group of pharmaceutical compounds or sympathomimetic drugs that mimic the effects of endogenous catecholamines such as epinephrine, norepinephrine, and dopamine. These drugs do not comprise a similar structure to catecholamines but still directly or indirectly activate the β2-adrenergic receptor. The first β-agonist was used around 5000 years ago in Chinese medicine where an ephedrine containing plant, Ma-huang, was used to treat respiratory problems [74]. Further research in the twentieth century has led to increased use of β-agonists for the treatment of respiratory diseases. The first β2-AR selective agonist, Salbutamol was synthesized by Glaxo in 1968 [75]. Later, the same team at Glaxo modified Salbutamol into Salmeterol with long-lasting effects and reduced side effects. Recently, they have synthesized β2-agonists with ultra-long-lasting effects such as Indacaterol [76]. After successful trials, these β2-agonists were approved by the US Food and Drug Administration (FDA) for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Since 1968, a number of companies have labored to develop β2-AR agonists, and some have now been commercialized for use in the treatment of COPD. A list of some of these agonists is given below and in \nTable 1\n.
\nA pharmacogenetic study of β2-agonists has summarized the relationship between polymorphisms in the β2-adrenoreceptor (ADRB2) gene and the effects of select β2-agonists [77]. Two hypotheses aim to account for the differences in functioning and in vivo half-lives of these compounds: exosite/exoreceptor or plasmalemma diffusion microkinetics. Briefly, the exosite hypothesis focuses on the ability of the side-chain of these compounds to interact with a distinct site on the receptor such that it allows the active component to “swing back-and-forth” to activate the receptor. The plasmalemma diffusion microkinetic hypothesis suggests that high concentrations of agonists are achieved in close proximity to the receptor and allows for a longer duration of action [78]. Both of these hypotheses require further investigation and need to be studied within the CNS. Depending upon their mechanism and duration of action, all β2-agonists are grouped into three major classes: short-acting, long-acting, and ultra-long-acting β2-agonists.
\nThese drugs are mostly hydrophilic in nature, access the active site of β-AR directly from the aqueous extracellular area and show the fast onset of action [79]. These SABAs bind to the receptor for short time; therefore, their duration of action is short. Some of the more common SABAs include Salbutamol (Ventolin), Albuterol (AccuNeb), Pirbuterol (Maxair), and Levalbuterol (Xopenex).
\nThese drugs are a frontline treatment for COPD, and usually prescribed alone or in combination with inhaled corticosteroids. LABAs are lipophilic in nature and taken up by cell membrane as a reservoir, progressively seep out and interact with the active site of the receptor [79]. They diffuse in the plasma membrane, where they interact with the active site of the β2-AR which allows for the close proximity with the receptor and longer duration of action. The onset of action of these drugs is slower as compared to SABAs, but the duration of action is prolonged thereby, called as LABAs. The duration of action is also dependent on the concentration of the agonist. Salmeterol, Salmeterol with an inhaled corticosteroid, Formoterol, and Formoterol with an inhaled corticosteroid are commercially available LABAs and used in medication for asthma and COPD [80].
\nThese agonists are also lipophilic in nature and onset of action is similar to LABAs, but the duration of action lasts longer than LABAs. Vilanterol with an inhaled corticosteroid and Indacaterol are ultra-LABAs, approved by FDA for the treatment of COPD [81].
\nDisease Condition | \nDesign | \nDoses | \nDrug | \nReferences | \n
---|---|---|---|---|
Spinal Cord Injury | \nRandomized controlled | \n4mg twice/day for 1st week then 8mg twice/day for 15 weeks | \nAlbuterol | \n[129] | \n
Alzheimer’s Disease | \nRandomized controlled | \n20mg/2ml for 12 months | \nFormoterol | \n[130] | \n
Multiple Sclerosis | \nBlinded controlled | \n4mg/day | \nAlbuterol | \n[131] | \n
Neuropathic pain | \nControlled, double blinded | \n5mg twice/day for 28 days | \nTerbutaline | \n[132] | \n
Memory and Cognition | \nRandomized controlled | \n4mg, single oral administration | \nSalbutamol | \n[133] | \n
SMA | \nUncontrolled | \n3-8mg/day for 6 months | \nAlbuterol | \n[134] | \n
ALS | \nUncontrolled | \n60ug/day for 6 months | \nClenbuterol | \n[135] | \n
SBMA | \nUncontrolled | \n20ug/day for 2days, then 40ug/day | \nClenbuterol | \n[136] | \n
Clinical trials using β2-agonist in neurological conditions.
\nSMA: Spinal Muscular Atrophy, SBMA: Spinal and Bulbar Muscular Atrophy, ALS: Amyotrophic Lateral Sclerosis.
The majority of adrenergic neurons are present in brainstem locus coeruleus (LC) nuclei, which is a predominant site for the production of norepinephrine (NE) in the brain. LC neurons play a key role in the regulation of cognitive behavior such as attention, mood, and arousal [82]. These neurons also play role in the development of the brain, mainly the neocortex [83]. The degeneration of LC-neurons has been identified in patients with PD and AD [84]. Also, the classical “monoamine hypothesis of depression” says that the deficiency of NE is a culprit for the cognitive impairment [85]. NE/noradrenaline, the primary neurotransmitter released by the LC neurons targets the adrenergic receptors present on the microglia and astrocytes in the brain [86]. NE-activated ARs on glial cells stimulate the second messenger system and maintain the homeostasis in the brain. Activation of AR on glial cells elicits anti-inflammatory actions, inhibits neuroinflammation, and thereby limits the degeneration of neurons [87]. Moreover, drugs that stimulate the release of NE/NA have potential to reduced inflammation and amyloid pathology in a mouse model of AD [88]. According to Braak’s hypothesis, early stage of progression starts in LC before it spreads to SN [89]. Overall, these and many other studies suggest the role of the adrenergic signaling in neurodegeneration. Therefore, enhancing NE/NA signaling, transplanting noradrenergic neurons, or use of drugs that mimic the activity of NA/NE on glial cells have great potential to reverse or halt the progressive degeneration of neurons [90]. The endogenous agonist/ligand for β2-AR is norepinephrine which acts as a neurotrophic factor and can influence protein/DNA synthesis in developing adult brain [91, 92]. NE protects cholinergic and dopaminergic cultured neurons against oxidative stress and catechol moiety of NE plays role in neuroprotection [93, 94]. It suggests that a compound containing catechol moiety, such as β-agonists, can mimic the neuroprotective effects of NE. Treatment with NE stimulates the synthesis of BDNF in astrocytes and neuron in vitro and in vivo [95, 96] and these neuroprotective effects were reversed by the antagonist of α1, β1, and β2-AR [97].
\nThe use of β2-agonists as an adjunct therapy to L-DOPA in PD was first described in 1994 [98]. Chai et al. showed that the β2-AR activation enhances hippocampal neurogenesis, ameliorates memory deficits, and increases dendritic branching and spine density in a mouse model of Alzheimer’s disease [99]. Recently, Mittal et al. have found that β2-AR activation regulates the gene expression of α-synuclein in various animal and in vitro models of PD. Salbutamol, a blood-brain-barrier-permeable β2-agonist, reduces expression of SNCA gene via histone-3-lysine-27 acetylation of its promoter and enhancer. They also analyzed the pharmacological history of 4 million Norwegians over 11 years and found that Salbutamol was also associated with reduced risk of developing PD [100]. In a mouse model of Down syndrome, Formoterol, a long-acting β2-AR agonist, causes significant improvement in synaptic density and cognitive functions [101]. Salmeterol (Sal) is an inhaled long-acting highly selective β2-AR agonist which is currently being used as the active ingredient in Advair@ as a bronchodilator. Our previous studies and others have shown that Salmeterol has anti-inflammatory and DA-neuroprotective activities, even at very low doses. Pre-treatment with Salmeterol protects DA neurons against LPS- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in both in vitro and in vivo animal models of PD [42, 102]. The mechanism how Salmeterol regulates the activation of microglia is described in \nFigure 1\n. Collectively, these studies suggest that β2-AR agonists not only protect neurons against degeneration, but also have anti-inflammatory effects, and therefore, hold significant promise for the treatments of a wide variety of neurodegenerative conditions including PD [43]. The clinical efficacy of β2-AR agonists have been examined in various neurological disorders and few of them are summarized in \nTable 2\n.
\nSchematic of microglia-mediated neurotoxicity and inhibitory effects of Salmeterol on microglial activation.
Extensive previous investigations into the etiology of PD demonstrate a central role for the inflammatory microglial cell in the progression of PD. Thus, targeting neuroinflammation mediated by microglia may serve as a potential therapeutic benefit in the treatment of PD. Since traditional treatment for PD is aimed only at controlling the disease symptoms, the search for more effective neuroprotective therapies which target the cause of the disease is now receiving significant attention. Studies targeting neuroinflammation are aimed to promote the development of a novel therapeutic approach and aid in the drug discovery for neurodegenerative conditions such as PD.
\nOne such anti-inflammatory approach that has been found to be effective in protection against dopaminergic neurodegeneration is accomplished by natural and therapeutic compounds that activate the β2-AR. Brain cells including neurons, microglia, and astrocytes as well as immune cells express a high density of β2-AR on their surface [66, 103]. Catecholamines such as epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine are the most abundant catecholamines found in the nervous system. As evidenced by many unrelated studies, catecholamines can modulate the immune response [87, 104]. Further studies have found that the endogenous agonist of β2-AR, norepinephrine (NE), controls microglial motility and functions during pathogenic conditions [105]. NE also protects cortical neurons against microglia-mediated inflammation, while decreased levels of NE enhance microglial activation [106]. One study showed that β2-AR negatively regulates NF-κB activation and stabilizes the NF-κB/IκBα complex via β-arrestin 2 in LPS activated murine macrophages [107]. Interestingly, activation of β2-AR in astrocytes modulates TNF-α-induced inflammatory gene expression in vitro and in vivo. In addition, an in vivo study demonstrated increased expression of β2-AR in glial cells in response to neuronal injury. This suggests that β2-AR may provide a therapeutic target for regulation of glial cell functioning and the inflammatory response in the brain [108]. Activation of β2-AR on astrocytes stimulates the release of trophic factors such as BDNF, bFGF, NGF-1, and TGF-β1 via canonical signaling, showing anti-apoptotic and neuroprotective effects in animal models of cerebral ischemia and excitotoxicity [109, 110]. It has also been shown that noradrenaline acting on β2-AR enhances the expression of anti-inflammatory and neurotrophic cytokine IL-10 in the brain. This suggests an endogenous ligand of β2-AR is neuroprotective during inflammatory conditions in CNS disease pathology [108, 111]. Both canonical and noncanonical signaling of β2-AR can selectively regulate the adaptive immune response [67], since β2-AR are expressed by naïve CD4+ T (T-helper (Th0)) and Th1 cells but absent on Th2 cells [112, 113]. Naïve CD4+ T-cell treated with a β2-AR agonist or NE suppresses the production of interferon (IFN)-γ and IL-2 and affects their differentiation [114]. Collectively, these studies and several others suggest the role of β2-AR in the regulation of immune response.
\nWe have characterized and examined the effects of β2-AR agonists including Salbutamol, Salmeterol, Indacaterol, and Vilanterol on neuroinflammation in models of PD in vitro and in vivo. However, the short-acting agonists were neuroprotective and able to reduce inflammation in vitro at higher doses, but the long-acting agonist showed beneficial effects at low concentration (10−9 M) in neurotoxicity and inflammatory models of PD. Salmeterol, a β2-AR agonist, can effectively serve as a therapeutic treatment for PD by inhibiting microglia-mediated inflammatory responses in vivo. We have found that Salmeterol functions to inhibit innate pro-inflammatory response in both murine macrophages and microglia through its inhibition of the NF-κB signaling pathways [42]. We have also investigated whether Salmeterol is specific to neuroinflammation in PD or if it can be used as a universal anti-inflammatory drug against other chronic inflammatory diseases. To test this, we used murine macrophages stimulated with LPS from Porphyromonas gingivalis (PgLPS), an oral pathogen as an in vitro model for the periodontal disease. We have found that Salmeterol shows similar anti-inflammatory effects on PgLPS-stimulated macrophages [115]. Additionally, Feng et al. have also shown neuroprotective effects of β-arrestin2 via endogenous opioid arrest in inflammatory microglial cells [116].
\nThe agonist-activated β2-AR stimulates MAPK signaling pathway via noncanonical and G-protein independent pathway. Agonist-activated β2-AR reduces phosphorylation of ERK1/2 and p38 MAPK in macrophages stimulated with LPS. In contrast, β2-AR activation stimulates MAPK signaling and TNF-α, IL-12, and NO production in murine macrophages treated with PMA (phorbol 12-myristate-13-acetate) [73]. Similarly, our previous studies have shown that activation of β2-AR with the high concentration of agonist (up to 10−5 M) leads to sustained phosphorylation of ERK1/2 and enhanced production inflammatory mediators in murine microglia and macrophages [117]. High-dose treatment of β2-AR agonists on mixed neuroglia culture enhances neurotoxicity via NADPH oxidase activity in the ERK-dependent manner [118]. Like others, we have found that the low-doses of the β2-AR agonist Salmeterol reduces the MAPK activity, NF-κB activation and production of TNF-α in LPS-activated primary microglia [42]. We have also found that low-dose Salmeterol inhibits the phosphorylation of TAK1 (TGF-β-activated kinase1) which is an upstream regulator of NF-κB signaling in LPS-stimulated microglia. We have also found that Salmeterol increases the expression of β-arrestin2 and enhances the interaction between β-arrestin2 and TAB1 (TAK1-binding protein), reduced TAK1/TAB1 mediated activation of NFκB and expression of pro-inflammatory genes. Furthermore, silencing of β-arrestin2 abrogates the anti-inflammatory effects of Salmeterol in LPS-stimulated BV2 cells [119]. These studies suggest that the anti-inflammatory effects of Salmeterol work through the inhibition of pro-inflammatory pathways in microglial cells.
\nPrevious findings show that high dose Salmeterol enhances the expression of IL-1β and IL-6 mRNA and protein in unstimulated human monocytes and murine macrophages. These effects were β-arrestin2-dependent but PKA and NF-κB independent, while treatment with ERK1/2 and p38 MAPK inhibitor could reverse this effect [117]. This finding and several others suggest Salmeterol or other long-acting agonist have β-arrestin “biased” signaling of β2-AR. These agonists activate receptors via β-arrestin signaling with a much greater extent than their effect on G-protein-dependent signaling [120]. Our studies suggest that a very low concentration of Salmeterol does not enhance cAMP signaling and its downstream mediators, while it activates the β-arrestin2-mediated signaling events [42]. β-arrestin2 has been shown as a novel regulator of IκB stability via the direct interaction of β-arrestin2 and IκB in HEK293 cells [121]. In addition, β-arrestin2 negatively regulates the activation of NF-κB via direct binding with IκBα [122]. One study showed that overexpression of β-arrestin2 significantly reduces L-DOPA-induced dyskinesia in animal models of PD [123]. Collectively, these studies suggest that β2-AR agonists can be used therapeutically not only to inhibit chronic inflammation and progressive degeneration of neurons, but also to treat some of the most debilitating neurologic symptoms in PD.
\nAfter binding with an agonist or endogenous ligand, β2-AR normally activates the classical cAMP-dependent signaling pathway. The downstream effect of the cAMP/PKA pathway is the phosphorylation and nuclear translocation of the CREB transcription factor which further enhances the expression of cAMP-inducible genes [79]. Activation of CREB via this pathway regulates the synthesis of proteins which are mandatory for neuronal homeostasis [124]. The classical signaling of β2-AR also increases the activity of PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha), which is a key regulator of mitochondrial biogenesis and ROS metabolism [125]. Activation of β2-AR also elevated the release of neurotrophic factors via cAMP/PKA/CREB pathway and provides neuroprotective benefits against degeneration [126]. An endogenous agonist of β2-AR (NE) affects immune cell functions, production of cytokines, and antibody secretion [112]. β2-AR agonists have anti-inflammatory activity and inhibit release of pro-inflammatory mediators via cAMP/PKA/CREB pathway and also by alternate cAMP-dependent pathway (cAMP/Epac1/2) [42, 127, 128]. We have also found that pro-inflammatory effects of high-dose of Salmeterol are through cAMP/Epac pathway, while the anti-inflammatory effects of low-dose of Salmeterol are independent on cAMP and Epac activation [42, 118].
\nThe β2-AR agonists discussed above are FDA-approved for the treatment of respiratory diseases such as asthma and COPD, but none of these β2-AR agonists are specifically developed for PD. Although, Mittal et al. have found in a Norwegian population that using Salbutamol, a SABA, lower the risk of developing PD whereas the use of Propranolol, a β2-AR antagonist (commonly used to treat hypertension and certain other forms of heart disease) was associated with increased risk of PD [100]. Furthermore, this risk of developing PD was dependent on the duration of Salbutamol intake in those patients. In the patient population who used Salbutamol for at least 6 months, it was expected that 43 would develop PD, but only 23 patients were ultimately diagnosed with the disease (rate ratio 0.66). On the other hand, in the cohort who used Salbutamol for 2 months or less, there was no decreased risk of developing PD in this population [100]. In contrast, patients on Propranolol (which is also used as therapeutic for tremors in PD) for at least 1 year showed a significantly increased risk of developing PD compared to patients not on propranolol (rate ratio 2.2). Therefore, it is clear that patients on long-term Salbutamol (a β2-AR agonist) had significantly decreased the risk of developing PD, while patients on long-term propranolol (a β2-AR antagonist) therapy had significantly higher rates of PD, suggesting that β2-AR inhibition is a highly significant risk factor in developing PD. When we compared the effectiveness of Salbutamol to Salmeterol (a more lipophilic drug) in animal models of PD, Salmeterol was much more effective both in vitro and in vivo in dopaminergic neuroprotection [42]. More importantly, we found that animals given Salmeterol treatment well before the appearance of symptoms in a long-term model of PD showed little evidence of dopaminergic neurodegeneration compared to untreated animals. Taken together, this data suggests that administration of β2-AR agonists may have a profound preventative effect on the development of PD. Since the blood-brain-barrier penetration is a major obstacle in the development of therapeutics targeting CNS disorders, it will be important to consider the importance of lipophilic properties, concentration within the CNS, as well as the specificity, half-life and safety in using β2-AR agonists in older patients before and after the initial appearance of symptoms associated with PD. Consequently, these drugs require further investigation in a large cohort study to assess their utility as a potential therapeutic for PD and other neurodegenerative diseases.
\nNatural or synthetic activation or inhibition of the β2-AR can have profound effects on the development and progression of Parkinson’s disease, a chronic neurodegenerative disorder which involves both neuroinflammatory and cellular mechanisms in dopaminergic neurotoxicity. It is now clear that the therapeutic use of β2-AR agonists can both inhibit the cause of neurodegeneration and activate a mechanism that can enhance recovery of patients with this disease, and serves as an important new therapeutic approach to the treatment of chronic neurodegenerative disorders.
\nAuthors declare no “conflict of interest.”
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