Studies investigating the relevance of endocannabinoid system in HD pathogenesis in animal models. Studies are presented in chronological order.
\\n\\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\\n\\n\\n\\n\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
\n\n\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"8855",leadTitle:null,fullTitle:"Retinoblastoma - Past, Present and Future",title:"Retinoblastoma",subtitle:"Past, Present and Future",reviewType:"peer-reviewed",abstract:"Retinoblastoma constitutes a global disease that burdens many families all over the world. This book highlights the essential basic information needed by every ophthalmologist and covers all aspects of this tumor: history, genetics, epidemiology, clinical features, diagnosis, imaging, management, and prognosis. The book includes basic knowledge, but is also designed to discuss current treatment modalities showing improved survival compared to the past. A whole chapter is dedicated to histopathological features and the American Joint Commission on Cancer staging system, with the aim of having it internationally used in all countries to improve outcomes and for research purposes. Readers will find the book enjoyable, comprehensive, and easy to understand.",isbn:"978-1-78984-791-8",printIsbn:"978-1-78984-790-1",pdfIsbn:"978-1-83962-791-0",doi:"10.5772/intechopen.81455",price:119,priceEur:129,priceUsd:155,slug:"retinoblastoma-past-present-and-future",numberOfPages:132,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"1686b2f1d697de9d4bc2005a5fa9b998",bookSignature:"Hind Manaa Alkatan",publishedDate:"November 13th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8855.jpg",numberOfDownloads:7300,numberOfWosCitations:9,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:15,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:30,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 15th 2018",dateEndSecondStepPublish:"March 6th 2019",dateEndThirdStepPublish:"May 5th 2019",dateEndFourthStepPublish:"July 24th 2019",dateEndFifthStepPublish:"September 22nd 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"223782",title:"Dr.",name:"Hind",middleName:"Manaa",surname:"Alkatan",slug:"hind-alkatan",fullName:"Hind Alkatan",profilePictureURL:"https://mts.intechopen.com/storage/users/223782/images/8837_n.jpg",biography:"Dr. Hind Manaa Alkatan, MD has completed her Saudi Ophthalmology Board (in the year 1994) from King Saud University (KSU), Riyadh, Saudi Arabia and her postdoctoral studies from Departments of Ophthalmology/Pathology, University of Manitoba and University of British Columbia, Canada (in the year 1999). She is an Associate Professor (College of Medicine), Consultant (Departments of Ophthalmology and Pathology), Chief of Ophthalmic Pathology Division, Director of the KSU Post-Graduate Residency & Fellowship Training Programs in Ophthalmology, and finally the Assistant Director for External Accreditation Unit, Postgraduate Medical Education Department, King Saud University, Riyadh, Saudi Arabia. She is a member in many international organizations in her field: Eastern Ophthalmic Pathology, Canadian Ophthalmology Society, International Society of Ocular Oncology, Ocular Oncology Group in addition to the local Saudi Ophthalmology Society. She contributes to other institutions such as being a Research Consultant at King Fahad Medical City in Riyadh. She has been contributing as an invited speaker in many international symposia such as the World Congress of Ophthalmology and the European Society of Pathology Annual meetings. She has published more than 140 papers in reputed journals and has been serving as an editorial board member for several journals including: Saudi Journal of Ophthalmology, World Journal of Ophthalmology, SRL Ophthalmology, The Scientific Pages of Ophthalmology and Academicians’ Research Center (ARC) Journal of Ophthalmology AJOM. \nAREAS OF INTEREST: \tEducation, Medical Research, Ophthalmic Pathology and Ophthalmic Oncology.",institutionString:"King Saud University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"191",title:"Ophthalmology",slug:"medicine-ophthalmology"}],chapters:[{id:"68882",title:"History and Genetics of Retinoblastoma",doi:"10.5772/intechopen.89035",slug:"history-and-genetics-of-retinoblastoma",totalDownloads:1023,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The history of retinoblastoma (RB) goes back to 1597 when Pieter Pawius of Amsterdam described a tumor that resembled retinoblastoma. “Fungus haematodes” was the first term used to describe retinoblastoma. Later, the American Ophthalmological Society approved the term retinoblastoma in 1926. The retinoblastoma protein is encoded by the RB1 gene located at 13q14. The functioning model of the tumor suppressor genes was first proposed by Alfred Knudson in the 1970s who precisely explained the hereditary mechanism of retinoblastoma. If both alleles of this gene are mutated, the protein is inactivated and this results in the development of retinoblastoma. One mutation can be either germline or somatic and the second one is always somatic. Differentiation between sporadic and germline retinoblastoma variants requires the identification of the RB1 germline status of the patient. This identification is important for assessing the risk of additional tumors in the same eye, the other eye, and the risk of secondary tumors. Thus, genetic testing is an important component of the management of all children diagnosed with retinoblastoma. In this chapter, we will go over the history, genetics, and counseling for patients with retinoblastoma.",signatures:"Tariq Alzahem, Waleed Alsarhani, Abdullah Albahlal, Leen Abu Safieh and Saad Aldahmash",downloadPdfUrl:"/chapter/pdf-download/68882",previewPdfUrl:"/chapter/pdf-preview/68882",authors:[null],corrections:null},{id:"67561",title:"Epidemiological and Genetic Considerations in Retinoblastoma",doi:"10.5772/intechopen.86811",slug:"epidemiological-and-genetic-considerations-in-retinoblastoma",totalDownloads:749,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Retinoblastoma (Rb) is the most common primary intraocular malignancy of childhood. The incidence of Rb is stable worldwide at one case per 16,000–18,000 live births. It is estimated that 7800–8800 Rb cases were newly diagnosed globally in 2017. Over 80% of these are in low- and middle-income countries (LMICs) in Asia and Africa. So far, there is no validated evidence that retinoblastoma incidence is associated with gender, ethnicity or geographical factors. A link between human papillomavirus (HPV) and Rb is being investigated to establish its role in the pathophysiology of the sporadic form of the disease. Survival rates for Rb vary greatly between countries: while almost all Rb cases from high-income countries survive, cases in LMICs have a mortality rate of up to 70%.",signatures:"Ido Didi Fabian, Faisal Al Qahtani and Covadonga Bascaran",downloadPdfUrl:"/chapter/pdf-download/67561",previewPdfUrl:"/chapter/pdf-preview/67561",authors:[null],corrections:null},{id:"66491",title:"Retinoblastoma: Presentation, Evaluation, and Diagnosis",doi:"10.5772/intechopen.85744",slug:"retinoblastoma-presentation-evaluation-and-diagnosis",totalDownloads:833,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Retinoblastoma was initially described in a case series by Dr. James Wardrop in 1809. Since then, the evaluation and diagnosis of retinoblastoma has progressed significantly, thus providing a framework for successful therapy with up to 97% survival rate in developed nations. Here we outline the presentation, evaluation, and detailed diagnostic steps of any child presenting with signs and symptoms of retinoblastoma (RB). We detail the questions and pertinent history to obtain, describe in detail the examination under anesthesia, ancillary testing, and recommendations for both anesthesia and neuroimaging. We also cover the differential diagnosis of retinoblastoma and the most common simulating lesions to present to an ophthalmologist. We describe the ways to determine if a patient has retinoblastoma or some simulating lesion, and the characteristics associated with each possibility. Finally, we briefly address genetic counseling and the next steps after diagnosis.",signatures:"Spencer T. Langevin and Brian P. Marr",downloadPdfUrl:"/chapter/pdf-download/66491",previewPdfUrl:"/chapter/pdf-preview/66491",authors:[null],corrections:null},{id:"67639",title:"Uses of Radiological Imaging in Retinoblastoma",doi:"10.5772/intechopen.86828",slug:"uses-of-radiological-imaging-in-retinoblastoma",totalDownloads:1015,totalCrossrefCites:2,totalDimensionsCites:7,hasAltmetrics:0,abstract:"Retinoblastoma is the most common primary ocular malignancy in children. Diagnosing retinoblastoma relies mainly on the clinical appearance of the lesion and not on histological description. Although histology still remains the gold standard in evaluation of tumor extension and progression risk factor, a tumor biopsy carries high risk of dissemination and is difficult to obtain. Retinoblastoma has characteristic clinical features of creamy-white mass associated with subretinal fluids and may be accompanied by retinal detachment and vitreous seeding. There are many factors contributing to metastatic risk factors like postlaminar optic nerve infiltration, scleral and choroidal invasion, and peribulbar fat invasion. Ancillary testing is necessary for any patient with a suspected retinoblastoma to assess the dimensions of the tumor as well as the tumor extension. An ultrasonography (B scan) will show the mass dimensions as well as the hyperechoic calcifications, which are commonly present with retinoblastoma. CT scan is not the modality of choice for diagnosis of retinoblastoma in children because of the radiation exposure. Magnetic resonance imaging is considered the examination of choice to assess the tumor extension as it has high soft tissue contrast. The use of MRI changed the accuracy of assessing metastatic risk factors as the results yielded before and after the use of MRI differed. This chapter will address the use of radiological imaging in retinoblastoma defining diagnostic characteristics and identifying parameters of metastatic risk factor assessment. This chapter will also include evidence-based review on the efficacy of radiological imaging of retinoblastoma and its impact on the choice of treatment and disease prognosis.",signatures:"Fahad Albader and Dalal Fatani",downloadPdfUrl:"/chapter/pdf-download/67639",previewPdfUrl:"/chapter/pdf-preview/67639",authors:[null],corrections:null},{id:"69132",title:"Retinoblastoma: Update on Current Management",doi:"10.5772/intechopen.88624",slug:"retinoblastoma-update-on-current-management",totalDownloads:961,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Retinoblastoma (Rb) is the most common primary intraocular malignancy in children with an incidence from 1:15,000 to 1:20,000 live births. It can present as a unilateral or bilateral involvement of the eyes. It is generally induced by biallelic mutation of the RB1 tumor suppressor gene that leads to malignant transformation of primitive retinal cells. The most common presentation is leukocoria, followed by strabismus. The initial assessment and future treatment of such tumor should be based on the laterality, the stage of the tumor, and the presenting age of the child. In general, the primary target of therapy is to preserve the child’s life. However, preserving the globe and preserving vision should be achieved whenever it’s possible. Retinoblastoma treatment has evolved from enucleating the affected globe to also involving external beam radiation therapy, cryotherapy, laser photocoagulation, thermotherapy, brachytherapy, and chemotherapy (intravitreal, intra-arterial, and systematic). This chapter is intended to discuss briefly the clinical presentation of Rb, as well as a comprehensive review about the evolution and current treatment modalities with a focus on cases with low-risk features.",signatures:"Abdullah Almater, Abdulrahman Alfaleh, Khalid Alshomar and Saleh AlMesfer",downloadPdfUrl:"/chapter/pdf-download/69132",previewPdfUrl:"/chapter/pdf-preview/69132",authors:[null],corrections:null},{id:"67646",title:"Retinoblastoma Management: Advances in Chemotherapy",doi:"10.5772/intechopen.86820",slug:"retinoblastoma-management-advances-in-chemotherapy",totalDownloads:806,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The treatment of children with retinoblastoma (RB) has evolved from primarily enucleation of the eye(s) to highly selective methods of chemotherapy administration and approach. Indulgent and comprehensive understanding of the multitude of factors including accurate classification and grading of disease, timing and response to therapy, when to consolidate with local methods of therapy, combination regimens to control systemic disease and prevent relapse while minimizing risk of secondary cancers are crucial factors in the management of children with retinoblastoma. Chemotherapy was introduced in the 1950s and has become an integral component in management of RB. Methods of administration range from systemic to locally directed therapy including; intravitreal, periocular and intra-arterial chemotherapy. This chapter is intended to discuss the evolution and current chemotherapeutic agents with various routes of administration. The indications, adverse occurrences, short- and long-term complications of both local and systemic treatments will be elucidated.",signatures:"Amani Al Kofide and Eman Al-Sharif",downloadPdfUrl:"/chapter/pdf-download/67646",previewPdfUrl:"/chapter/pdf-preview/67646",authors:[null],corrections:null},{id:"69287",title:"Histopathological Characteristics and Classification for Prognostic Indicators",doi:"10.5772/intechopen.89410",slug:"histopathological-characteristics-and-classification-for-prognostic-indicators",totalDownloads:1172,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Retinoblastoma (RB) is the most common intraocular tumor in children. It arises from the nuclear layer of the retina, with different growth patterns: endophytic, exophytic, and mixed. Retinoblastoma also has characteristic histopathological appearance with areas of viable tumor, necrosis, and calcifications. The tumor differentiation can be determined by the presence of rosettes—Flexner-Wintersteiner rosettes as well as fleurettes—and tends to become less differentiated with age. Histopathological risk factors are used as prognostic indicators and will be discussed in this chapter together with the typical tissue diagnostic features. These will include optic nerve/choroidal invasion, extraocular extension, and anterior segment involvement. Other prognostic factors with less impact will be discussed as well including the amount of necrosis, mitotic figures, and grading of anaplasia. Furthermore, we will briefly discuss different regression patterns and posttreatment findings in enucleated globes.",signatures:"Heba Alsharif, Hala Helmi and Azza Maktabi",downloadPdfUrl:"/chapter/pdf-download/69287",previewPdfUrl:"/chapter/pdf-preview/69287",authors:[null],corrections:null},{id:"67508",title:"Secondary Malignancies in Adulthood and after Retinoblastoma Treatment in Childhood",doi:"10.5772/intechopen.86746",slug:"secondary-malignancies-in-adulthood-and-after-retinoblastoma-treatment-in-childhood",totalDownloads:745,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Advances in retinoblastoma treatment in children nowadays and in the last decades lead to success and adulthood life without problems. Treatment modalities used in childhood to cure the retinoblastoma can affect health later. Some secondary malignancies in patients with retinoblastoma may be long-term side effects of radiation and chemotherapy. However, rates of second cancers in people treated for hereditary retinoblastoma are higher than in people who had sporadic retinoblastoma. The survivors of retinoblastoma in whom second malignant neoplasms develop are at a higher risk for the development of additional tumors than they were for the development of a second tumor. The standardized incidence rate of secondary malignancies is about 15% in inherited cases and about 1.5% in nonheritable retinoblastoma. However, today there is no clear consensus on what, if any, screening protocol would be most appropriate and effective.",signatures:"Alena Furdova and Juraj Sekac",downloadPdfUrl:"/chapter/pdf-download/67508",previewPdfUrl:"/chapter/pdf-preview/67508",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6372",title:"Early Events in Diabetic Retinopathy and Intervention Strategies",subtitle:null,isOpenForSubmission:!1,hash:"46ff48bdb1bac8a69372566fff0e2f6d",slug:"early-events-in-diabetic-retinopathy-and-intervention-strategies",bookSignature:"Andrew T.C. Tsin and Jeffery G. 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Huntington’s disease (HD) is a neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline as well as psychiatric disturbance [1, 2]. The prevalence of HD is estimated to be between 0.4 and 5.70 per 100,000. Since HD is a genetic disorder, the prevalence depends strongly on the study population and it is higher in Europe, North America, and Australia than in Asia [3]. HD is caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). The disease develops in individuals bearing a number of repetitions greater than 40, whereby greater CAG repeats found in the huntingtin gene are associated with early-onset forms of the disorder, fast rate of disease progression, and the most severe neurological deficits [4].
The mean age of HD onset is around 40 years, meanwhile the Juvenile Onset Huntington’s Disease (JOHD), occurs in individuals bearing more than 60 CAG repeats, which usually starts at the age of 21. HD eventually leads to death 15–20 years after the symptomatic onset [5]. It is believed that mutant huntingtin (mHTT) affects many cellular functions and leads to cell death, preferentially subpopulations of GABAergic medium spiny projection neurons and neurons in the cerebral cortex [1, 6]. This leads to imbalances in diverse neurotransmission, including the dopaminergic (DA) and glutaminergic systems. In the early stages of HD, DA neurotransmission is increased, whereas expression of DA receptors is reduced. However, in the course of the disease DA neurotransmission decreases. In turn, time-dependent abnormal DA neurotransmission affects glutamate receptor modulation, which may cause excitotoxicity [7, 8]. As DA plays a crucial role in the control of coordinated movements, motivation, and reward as well as cognitive function, alterations in DA balance in the striatum and provoke neurological and psychiatric symptoms of HD. The early stages of the disease are often characterized by chorea, followed by akinesia, while dystonia is more typical for the late stages [9]. Major non-motor symptoms include apathy and depression, anxiety, irritability, or aggressive behavior [9]. Impairment in cognitive functioning eventually ending in dementia, which has been mentioned by George Huntington in his first report, is another integral part of the disease [10]. Until today, there is no cure for HD, and treatment is only symptomatic, targeting mainly dopaminergic and glutaminergic systems [11].
Over the last 30 years, the endocannabinoid system (ECS) has emerged as an important neuromodulatory system, which could be efficiently targeted in a number of neurological diseases, including HD [8, 12, 13]. The primary cannabinoid receptor subtypes are cannabinoid receptors type 1 (CB1) and type 2 (CB2). The CB1 receptor is a protein-coupled receptor, highly expressed in the central nervous system (CNS), particularly in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem. In addition to its CNS location, CB1 has also been identified in numerous peripheral tissues and cell types [14]. On the other hand, the CB2 receptor is expressed mainly outside CNS, predominantly in the immune system. However, it has also been identified in the CNS, especially in the glial cells and brainstem neurons [15, 16]. The abovementioned high distribution of the CB1 receptor in basal ganglia indicates an indispensable role of the ECS in the control of movements by inhibitory modulation of other neurotransmitter systems [16]. Moreover, the CB1 receptors regulate glutamatergic neurotransmission under both physiological and pathological conditions and thus are able to downregulate excitotoxic glutamate release [17].
Studies in animal models suggest that the pathogenesis of HD may be related to an early and widespread reduction in the ECS, particularly to the loss of CB1 receptors [16, 18, 19] and decreased endocannabinoid levels in the striatum, which in turn may lead to hyperkinesia [19]. The administration of substances, which increase endocannabinoid activity led to a significant improvement of motor disturbances in a rat model of HD [16, 20]. In particular, Lastres-Becker et al. [17] hypothesized that substances that increase the endocannabinoid activity could be applied for the treatment of hyperkinetic symptoms. To test this hypothesis the authors created a rat model of HD through bilateral striatal injections of 3-nitropionic acid that leads to impaired striatal GABAergic neurotransmission. As a result, these rats started suffering from abnormal movements followed by motor depression. In addition, they demonstrated that the severity of motor hyperkinesias was correlated with decreased concentration of several neurotransmitters, such as GABA, dopamine, and their metabolites. Moreover, mRNA levels for the CB1 receptor were depleted in the caudate-putamen of 3-nitropropionic acid (3-NP) injected rats. In addition, the authors demonstrated a reduction in CB1 receptor binding in the caudate-putamen, the globus pallidus, and also substantia nigra. Finally, the administration of AM404, an inhibitor of endocannabinoid uptake, led to the alleviation of motor disturbances. The same group from Madrid [21] explored the status of CB1 receptors in the HD94 transgenic mouse model of HD. To investigate this problem, the authors analyzed mRNA levels of the CB1 receptor and the number of specific binding sites, and the activation of GTP-binding proteins by the CB1 receptor agonist. As a result, they have demonstrated that mRNA transcripts of the CB1 receptor were significantly decreased in selected regions of the brain, such as caudate in the HD transgenic mice compared to controls. This depletion was correlated with a marked reduction of reception density in the caudate, globus pallidus, and substantia nigra pars reticulata. In addition, the efficacy of CB1 receptor activation was depleted in the globus pallidus and there was a trend toward a decrease in substantia nigra.
Another significant contribution was done by the group from the Autonomous University in Madrid led by Isabel Lastres-Becker [22]. The scientists used a previously mentioned rat model of HD for this purpose created via bilateral intrastriatal injections of 3-NP. As a result, CB1 receptor binding and activation of GTP-binding proteins were also reduced in the basal ganglia. In parallel, the authors demonstrated a significant decrease of two endocannabinoids, anandamide and 2-arachidonoylglycerol in the striatum of affected rats, while there was an increase in anandamide concentration in the substantia nigra. Importantly, both CB1 receptors concentration, as well as endocannabinoid levels, were not changed in the cerebral cortex. Another study by the same group [23] has shown that compounds acting at the endocannabinoid systems reduce hyperkinesia in a rat model of HD. In particular, they applied AM404, an inhibitor of the endocannabinoid reuptake, which was able to reduce hyperkinesia and provoke recovery from neurochemical deficits.
As for exocannabinoids used in the treatment of neurological and psychiatric disorders, in one study [24], delta9-tetrahydrocannabinol (THC), a nonselective cannabinoid receptor agonist, and SR141716, a selective antagonist for the CB1 receptor, were tested in an animal model of HD. Surprisingly enough, the administration of THC increased malonate-induced striatal lesions, but SR141716 enhanced the same effect to an even greater extent. Another study examined the long-term effects of exocannabinoid exposure in animal models of HD. In this case, they used transgenic mice R6/1 of HD and administered THC for 8 weeks. This chronic treatment preserved CB1 receptors in the R6/1 striatum, suggesting that the manipulation of endocannabinoid levels warrants further exploration.
Similarly, Sagredo et al. [25] examined the neuroprotective effect of cannabinoids in rats with 3NP striatal lesions. To tackle this question, the authors used the CB1 agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 agonist HU-308, and cannabidiol (CBD). Interestingly enough, the application of CBD, but not ACEA or HU-308 reversed the effects of 3NP. In particular, CBD reversed 3NP-induced reductions in GABA contents and mRNA levels of substance P (SP), neuronal-specific enolase (NSE), and superoxide dismutase-2 (SOD-2). The authors concluded that CBD has neuroprotective values, but mainly on striatal neurons projecting to substantia nigra. This neuroprotective effect was not reversed by the CB1 receptor antagonist SR141716. Pintor et al. [26] demonstrated that the cannabinoid receptor agonist, WIN 55,212–2, attenuates the effects induced by quinolinic acid (QA) in the rat striatum. In this study, QA was introduced in the rat striatum and this, in turn, led to the reproduction of clinical features typical for HD. The administration of WIN 55,212–2 blocked the increase in extracellular glutamate induced by QA. During
Another study by de Lago et al. [29] examined whether arvanil, an endocannabinoid „hybrid,” could lead to symptom reduction in the rat model of HD. It was demonstrated that arvanil reduced ambulation and stereotypic movements. The same group [30] demonstrated that UCM707, an inhibitor of the anandamide uptake, could be used as a symptom control agent in an animal model of HD and multiple sclerosis (MS), but failed to delay the disease progression.
Furthermore, a number of other studies have suggested that therapies with CB-activating compounds might lead to neuroprotective effects against excitotoxic striatal toxicity through both CB receptor-mediated and independent effects [21, 31, 32, 33, 34, 35]. However, in several studies, no benefit or even exacerbation of neurotoxicity could be observed [22, 25, 29].
An overview of studies investigating the relevance of the endocannabinoid system in HD pathogenesis in animal models is shown in Table 1.
Reference | Model | Substance | Outcome |
---|---|---|---|
Lastres-Becker et al. [17] | 3 NP rats |
| AM404 reduced motor hyperactivity and improved toxin-induced GABA and dopamine deficits. |
Lastres-Becker et al. [23] | 3 NP rats |
| AM404 reduced hyperkinesia in lesioned animals VDM11 and AM374 did not improve hyperkinesia. Capsaicin and CP55,940 reduced hyperkinesia. Capsaicin improved GABA and dopamine deficits in basal ganglia. |
Lastres-Becker et al. [24] | Malonate rats |
| Exacerbation of neurotoxicity. |
Lastres-Becker et al. [36] | 3NP rats |
| Neuroprotection. |
De Lago et al. [21] | 3 NP rats |
| Arvanil showed anti-hyperkinetic effects and increased the content of glutamate in the globus pallidus. |
Pintor et al. [26] | Quinolinic acid rats |
| WIN55,212-2 showed neuroprotective effects and AM-251 reversed them. |
De Lago et al. [30] | Malonate rats |
| Reduction of hyperkinetic activity and increase both glutamate and GABA levels in the globus pallidus. No neuroprotection. |
Sagredo et al. [25] | 3 NP rats |
| Neuroprotection. |
Sagredo et al. [28] | 1. Malonate mice 2. CB2R knockout mice |
| HU-308 was neuroprotective and reduced proinflammatory markers (TNF-alpha). These effects were reversed by SR144528. CBD and ACEA were not neuroprotective. |
Palazuelos et al. [35] | Mice expressing mHTT or quinolinic acid exposure |
| HU-308 reduced quinolinic acid neurotoxicity. |
Sotter et al. [34] | Pheochromocytoma cells expressing mHHT |
| HU210 caused small, but significant increase of cell survival. It excerted potentially toxic effects including increased huntingtin aggregation. |
Dowie et al. [37] | R6/1 transgenic mice |
| HU210 and THC did not improve motor symptoms. HU210 treatment was associated with seizures. |
Valdeolivas S et al. [27] | Malonate rats |
| THC/CBD was neuroprotective. SR141716 and AM630 reduced its neuroprotective effects |
Studies investigating the relevance of endocannabinoid system in HD pathogenesis in animal models. Studies are presented in chronological order.
HD: Huntington disease; CB1R: cannabinoid receptor type 1; CB2R: cannabinoid receptor type 2; 3 NP mice: 3-nitropropionic acid; eCBRI: endocannabinoid re-uptake inhibitor; TRPV1: the transient receptor potential cation channel subfamily V member 1
The post-mortem examination of brain tissue in individuals with HD as well as PET imaging studies
First reports of using cannabinoids in patients with HD were contradictory [24, 28, 30]. In 1991, Consroe et al. conducted the first double-blind randomized cross-over study to evaluate the efficacy and safety of oral CBD (10 mg/kg/day for 6 weeks) in 15 neuroleptic-free patients with HD [28]. The therapeutic response was evaluated with the use of the Marsden and Quinn chorea severity scale [40]. In this study, no statistically significant improvement has been shown. There was also no significant difference between the CBD and placebo groups in terms of side effects. In 1999 Müller-Vahl et al. published a case of a 58-year-old male with HD who was treated with a single dose of 1.5 mg of a CB1 agonist, nabilone. In this individual, a severe deterioration of chorea was observed [24]. In 2006, Curtis et al. described a case of a 43-year-old female, whose chorea and irritability improved after medication with 1 mg of nabilone [30]. A double-blind placebo-controlled randomized cross-over trial using nabilone was conducted in 2009 by the same author. This time 37 patients were treated with 1 mg or 2 mg of nabilone daily for 5 weeks. For primary measures, the patients were assessed with Unified Huntington’s Disease Rating Scale (UHDRS) total motor score and UHDRS subsections for chorea, cognition and behavior, and neuropsychiatric inventory (NPI) for secondary measures. There were no statistically significant differences in total UHDRS between the groups. However, statistically, significant improvements were noted for the UHDRS chorea scale and the neuropsychiatric inventory. There were no statistical differences reported between the 1 and 2 mg. Adverse effects were reported for placebo and nabilone similarly. There was one Serious Adverse Event (SAE) related to nabilone—one of the patients withdrew due to severe sedation. Importantly, no psychoses were reported [23]. In 2016, the results of a study conducted by Moreno et al. using nabiximols in the treatment of HD were published [36]. Nabiximols (tradename
An overview of all available studies investigating the efficacy and safety of CBM in HD is provided in Table 2.
Reference | Number of patients (sex) | Age (mean) | Substance | Study design | Outcome |
---|---|---|---|---|---|
Consroe et al. [41] | 15 (8 male, 7 female) | No data | CBD | Double-blind, randomized cross-over study | No significant improvement No relevant side effects |
Müller-Vahl et al. [42] | 1 male | 58 | Nabilone | Case report | Deterioration of chorea |
Curtis et al. [43] | 1 female | 43 | Nabilone | Case report | Improvement of chorea and irritability |
Curtis et al. [44] | 44 (22 male, 22 female) | 52 | Nabilone | Double-blind, placebo-controlled, cross-over study | Improvement of the UHDRS-chorea; 1 SAE – sedation |
Moreno et al. [45] | 25 (14 male, 11 female) | 47.6 | Nabiximols | Double-blind, randomized, cross-over, placebo-controlled, pilot trial | No SAE or clinical worsening; no significant improvement; no significant changes of biomarkers |
An overview of studies investigating efficacy and safety of CBM in HD.
CBM: cannabis based medicine; HD: Huntington disease; SAE: severe adverse events; CBD: cannabidiol; UHDRS: United Huntington Disease Rating Scale; and SAE: serious adverse events.
Even today, very little is known about the safety of CBM in patients with HD due to the limited number of studies exploring this issue. However, the available preliminary results suggest that the safety profile of CBM in HD is similar to that in other groups of patients. A recently conducted meta-analysis, including diverse populations of patients treated with CBM, showed that administration of cannabinoids can be associated with a greater risk of adverse events (AE), including serious adverse events (SAE) [46]. The most common short-term AEs included dizziness, dry mouth, nausea or vomiting, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucinations. So far, there has been no study evaluating the long-term AEs of cannabinoids [46]. Up to this point, only two CBM-related SAEs in HD have been reported and both occurred after the treatment with nabilone. A 58-year-old male described by Müller-Vahl experienced an exacerbation of chorea. Moreover, the patient noticed the deterioration of short-term memory [42]. During the study performed by Curtis et al. [44], one of the patients experienced severe sedation and had to withdraw from the trial. Importantly, none of the patients enrolled in this study suffered from exacerbation of chorea or psychosis. The most frequent AE was drowsiness and forgetfulness. In the recent study conducted by Moreno et al. [45], dizziness or disturbance in attention were the two most common AEs. No serious alterations in psychiatric or neurological conditions of the participants were noted [45].
There is increasing evidence that the endocannabinoid system is a new promising therapeutical target in patients with HD. However, larger well-designed controlled studies are urgently needed to confirm the efficacy and safety of this treatment.
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\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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