Reference strains used in this study.
\r\n\tCongenital hearing loss means hearing loss that is present at birth. I have managed children with hearing loss for many years, and the most touching thing is the light that blooms on the face while the hearing-impaired child heard his mother's voice at first time. The scene of "happy tears" impressed me so much. To hear the voice that has not been heard is so pleasant, as if this ordinary listening experience is a supreme listening enjoyment.
\r\n\r\n\tAge-related hearing loss means a progressive loss of ability to hear high frequencies with aging, also known as presbycusis. Among them are the influence of internal and external factors such as genes, drugs and noise exposure. The studies pointed out that the brain stimulation of the hearing-impaired person is greatly reduced compared with subjects with normal hearing. The connection of auditory cortex and other brain areas has declined a lot, which is probably one of the important causes of dementia or even depression in the elderly.
\r\n\r\n\tNoise-induced hearing loss is hearing impairment resulting from exposure to loud sound. There is actually continuous and endless noise in many workplaces, which may cause chronic and cumulative damage. Some young people often work hard but easily neglect to protect themselves. In addition, in recent years, entertainment noise (such as nightclubs, concerts, and personal listening devices) has caused hearing impairment in young people. These should be avoidable and preventable.
\r\n\r\n\tHearing Science is the study of impaired auditory perception, the technologies and other rehabilitation strategies for persons with hearing loss. Public health has been defined as "the science and art of preventing disease", improving quality of life through organized efforts. To avoid the “epidemic” of hearing loss, it is necessary to promote early screening, use hearing protection, and change public attitudes toward noise.
\r\n\r\n\tBased on these concepts, the book incorporates updated developments as well as future perspectives in the ever-expanding field of hearing loss. Besides, it is also a great reference for audiologists, otolaryngologists, neurologists, specialists in public health, basic and clinical researchers.
",isbn:"978-1-83968-678-8",printIsbn:"978-1-83968-677-1",pdfIsbn:"978-1-83968-679-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"a4b7dbb02ba00e7412422cd5dbffa029",bookSignature:"Dr. Tang-Chuan Wang",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10529.jpg",keywords:"Hidden Hearing Loss, Plasticity, Electrophysiology, Otoacoustic Emission, Newborn Hearing Screening, Genetics, Aging, Hearing Aids, Noise Exposure, Occupational Hearing Loss, Epidemiology, Prevention",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 3rd 2020",dateEndSecondStepPublish:"October 1st 2020",dateEndThirdStepPublish:"November 30th 2020",dateEndFourthStepPublish:"February 18th 2021",dateEndFifthStepPublish:"April 19th 2021",remainingDaysToSecondStep:"4 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Tang-Chuan Wang is an excellent otolaryngologist-head and neck surgeon in Taiwan; a research scholar of Harvard Medical School and University of Iowa Hospitals. He worked in the Hospital of the University of Pennsylvania, Boston Children's Hospital, and Massachusetts Eye and Ear. Due to his contribution to biomedical engineering, he was invited into the executive committee of HIWIN-CMU Joint R & D Center in Taiwan.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"201262",title:"Dr.",name:"Tang-Chuan",middleName:null,surname:"Wang",slug:"tang-chuan-wang",fullName:"Tang-Chuan Wang",profilePictureURL:"https://mts.intechopen.com/storage/users/201262/images/system/201262.gif",biography:'Dr. Tang-Chuan Wang is an excellent otolaryngologist – head and neck surgeon in Taiwan. He is also a research scholar of Harvard Medical School and University of Iowa Hospitals. During his substantial experience, he worked in Hospital of the University of Pennsylvania, Boston Children\'s Hospital and Massachusetts Eye and Ear. Besides, he is not only working hard on clinical & basic medicine but also launching out into public health in Taiwan. In recent years, he devotes himself to innovation. He always says that "in theoretical or practical aspects, no innovation is a step backward". Due to his contribution to biomedical engineering, he was invited into executive committee of HIWIN-CMU Joint R & D Center in Taiwan.',institutionString:"China Medical University Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"China Medical University Hospital",institutionURL:null,country:{name:"Taiwan"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"7461",title:"Management of Tinnitus",subtitle:"The Enriching Views of Treatment Options",isOpenForSubmission:!1,hash:"9626e5a89247b934de503a3d08752e14",slug:"management-of-tinnitus-the-enriching-views-of-treatment-options",bookSignature:"Tang-Chuan Wang",coverURL:"https://cdn.intechopen.com/books/images_new/7461.jpg",editedByType:"Edited by",editors:[{id:"201262",title:"Dr.",name:"Tang-Chuan",surname:"Wang",slug:"tang-chuan-wang",fullName:"Tang-Chuan Wang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7245",title:"Challenging Issues on Paranasal Sinuses",subtitle:null,isOpenForSubmission:!1,hash:"67a331ebb2dd2b8f73228fa4daa7382f",slug:"challenging-issues-on-paranasal-sinuses",bookSignature:"Tang-Chuan Wang",coverURL:"https://cdn.intechopen.com/books/images_new/7245.jpg",editedByType:"Edited by",editors:[{id:"201262",title:"Dr.",name:"Tang-Chuan",surname:"Wang",slug:"tang-chuan-wang",fullName:"Tang-Chuan Wang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"52588",title:"Survey of Cutaneous Leishmaniasis in Mexico: Leishmania Species, Clinical Expressions and Risk Factors",doi:"10.5772/65501",slug:"survey-of-cutaneous-leishmaniasis-in-mexico-leishmania-species-clinical-expressions-and-risk-factors",body:'Leishmaniasis is a group of clinical entities present in 79 countries at a rate of 400,000 cases per year. The World Health Organization estimates a worldwide prevalence of approximately 12 million cases with population at risk of approximately 350 million. It is caused by a parasitic protozoan, which belongs to the Leishmania genus that is transmitted to human beings and animal reservoirs by phlebotomine sand flies [1].
Cutaneous leishmaniasis (CL) is the most widespread form, causing primary localized skin lesions from which parasites can disseminate to the nasopharyngeal mucosa and cause mucocutaneous leishmaniasis (MCL) or disseminate to the entire body as nodular lesions in diffused cutaneous leishmaniasis (DCL). Visceral leishmaniasis (VL) is the most severe form of the disease; according to the WHO in areas endemic for VL, many people have asymptomatic infection and a concomitant HIV infection increases the risk of developing active VL by between 100 and 2320 times [1].
VL is characterized by irregular fever, weight loss, swelling of the liver and spleen, and anemia. After recovery, patients sometime develop chronic DCL [2, 3].
American cutaneous leishmaniasis is characterized by a spectrum of clinical presentations caused by Leishmania species grouped in complexes; these include LCL caused by Leishmania (L.) mexicana; DCL caused by Leishmania amazonensis, Leishmania venezuelensis, and Leishmania pifanoi, all of them belonging to the L. mexicana complex; and MCL caused by members of the L. braziliensis complex. VL is caused by L. (L.) chagasi belonging to the L. donovani complex. Symptomatic diagnosis confuses CL with unrelated disorders such as tropical ulcers, sporotrichosis, leprosy, and skin cancer, among others [4].
In Mexico, Seidelin first recorded LCL caused by L. (L.) mexicana in 1912, who called it “chiclero’s ulcer,” because he found the disease in rubber workers. CL is distributed in three main endemic areas: Gulf of Mexico, Pacific of Mexico, and Central Mexico. In these regions, multiple species of Leishmania may coexist and several species can cause both LCL and MCL [5–7]. Several methods of detection of Leishmania based on deoxyribonucleic acid (DNA) have been described. The polymerase chain reaction (PCR) has been employed for selective amplification of Leishmania DNA. Several molecular targets for a diagnostic PCR have been evaluated including the minicircle kinetoplast DNA (kDNA), the miniexon (spliced leader RNA) gene, and the internal transcribed spacer (ITS) [8–10], among others.
In order to find a diagnostic method for leishmaniasis that combines high sensitivity with species differentiation in the field, rapid diagnosis, and low cost, several molecular targets for a diagnostic PCR were evaluated from patients with cutaneous ulcers suspected of having LC from several endemic areas. The target was minicircle kinetoplast DNA (kDNA) using specific primers or probes with the PCR and Southern or dot blotting [11] and PCR-RFLP of the internal transcribed spacer 1 (ITS1) [10, 12].
Distribution of CL or VL in social, educative, and ecological conditions was recorded. The patients diagnosed with CL were treated with meglumine antimoniate (Glucantime®).
In these studies, we evaluated samples from patients with clinical symptoms and skin lesions suggestive of CL, MCL, and DCL from several endemic areas of Mexico—Campeche, Tabasco, Veracruz, Nayarit and Chiapas, and Quintana Roo—or samples from VL patients from Chiapas and Tabasco states. The clinical samples were taken on filter papers or smears, needle aspirates, and tissue biopsy samples (1–2 mm) from the edge of cutaneous or bone marrow aspirates (Figure 1).
Map of Mexico, showing the Ocean Pacific, Gulf of Mexico, and Central Leishmaniasis endemic regions.
For bleeding human beings for diagnosis and therapeutics, informed consent was obtained from all the adults who participated in the study. Consent for including young children was obtained from their parents or guardians. The ethics committee of the corresponding health authorities, in agreement with International Ethical Guidelines for Biomedical Research involving human subjects (Norma Oficial Mexicana de Salud: NOM-003-SSA 2-1993), reviewed and approved the protocols of the present studies.
Reference Leishmania strains (Table 1), used as control and Mexican isolates of Leishmania from Tabasco, Veracruz, Campeche, and Quintana Roo states (Table 2 and Figure 1), were cultured in Roswell Park Memorial Institute medium 1640 (RPMI medium 1640) supplemented with 10% fetal calf serum at 26°C. DNAs of Trypanosoma cruzi and Mycobacterium tuberculosis were used as negative controls.
Number | Strain | Code | Leishmania species |
---|---|---|---|
1 | MHOM/BZ/82/BEL21 | BEL21 | L. (L.) mexicana |
2 | MHOM/BZ/62/M379 | M379 | L. (L.) mexicana |
3 | IFLA/BR/67/PH8 | PH8 | L. (L.) amazonensis |
4 | MHOM/BR/73/M2269 | M2269 | L. (L.) amazonensis |
5 | MHOM/PE/84/LC53 | LC53 | L. (V.) braziliensis |
6 | MHOM/BR/84/LTB300 | LTB300 | L. (V.) braziliensis |
7 | MHOM/BR/75/M2903 | M2903 | L. (V.) braziliensis |
8 | MHOM/BR/75/M2904 | M2904 | L. (V.) braziliensis |
9 | MHOM/BR/75/M4147 | M4147 | L. (V.) guyanensis |
10 | MHOM/PE/84/LC26 | LC26 | L. (V.) peruviana |
11 | MHOM/CR/87/NEL3 | NEL3 | L. (V.) panamensis |
12 | MHOM/PA/72/LS94 | LS94 | L. (V.) panamensis |
13 | MHOM/IN/80/DD8 | DD8 | L. (L.) donovani |
14 | MHOM/BR/74/PP75 | PP75 | L. (L.) infantum/chagasi |
Reference strains used in this study.
Number | Code | Origin | Clinical expression | Leishmania species |
---|---|---|---|---|
1 | MHOM/MX/88/HRC JS | Tabasco | DCL | L. am + L. mex |
2 | MHOM/MX/88/HRC MC | Tabasco | LCL | L. (L.) mexicana |
3 | MHOM/MX/84/ISET GS | Tabasco | DCL | L. am + L. mex |
4 | MHOM:MX:83:UAVY CV | Yucatan | LCL | L. (L.) mexicana |
5 | MHOM/MX/85/ISET HF | Veracruz | DCL | L. am + L. mex |
6 | LVER | Veracruz | DCL | L. am + L. mex |
7 | REP | Campeche | LCL | L. am + L. mex |
8 | MHM/MX/06/ENCB/MIC | Campeche | LCL | L. (L.) mexicana |
9 | MHM/MX/06/ENCB CDL | Campeche | LCL | L. (L.) mexicana |
10 | MHM/MX/06/ENCB FDL | Campeche | LCL | L. (L.) mexicana |
11 | CR | Campeche | LCL | L. (V.) braziliensis |
12 | PVS | Campeche | LCL | Mx. L. mexicana |
13 | RGL | Campeche | LCL | L. b + L. mx |
14 | FJJ | Campeche | LCL | L. b + L. mx |
15 | ESP | Campeche | LCL | Mx. L. mexicana |
Mexican isolates of Leishmania analyzed in this study.
L. am + L. mex, L. (L.) amazonensis + L. (L.) mexicana; L. b + L. mx, L. braziliensis + L. mexicana; Mx. L. mexicana, Mexican variant of L. (L.) mexicana
Clinical specimens cut from the filter paper or eluted from the smear, bone marrow aspirates, skin aspirates, and tissue biopsy samples (1–2 mm) were incubated in 250 μL of cell lysis buffer for 1 h at 56°C. DNA from Leishmania cultures was prepared by centrifuging 109 parasites in the exponential phase of growth at 2000 × g for 10 min at 4°C. The DNA was extracted from the pellet using the High Pure PCR template preparation kit (Roche Diagnostics GmbH, Mannheim, Germany), following the manufacturer’s instructions. The DNA was stored at −20°C until used.
PCR analysis of kDNA for subgenus Leishmania was carried out by using the AJS1 and DeB8 primers [13]. PCR of the L. mexicana complex was carried out using the M1 and M2 primers [14] and the LMO1 and LMO2 primers specific for minicircles of Mexican L. (L.) mexicana strains [15]). PCR of the L. braziliensis complex was done with the B1 and B2 primers [8]. PCR for L. donovani complex was done with the D1 and D2 primers [16]. PCR amplification conditions were performed as described previously [8, 13, 14, 16, 17].
PCR species specific for nuclear DNA from variants of L. (V.) braziliensis was carried out by using the primers 3J1 and 3J2. Amplification conditions were as described elsewhere [18].
Some samples were analyzed for ITS1 PCR using the primers: LITSR and L5.8S [10]. Amplification conditions were as described [12]. PCR products were digested with HaeIII enzyme, according to the manufacturer’s instructions. The amplicons and restriction products were analyzed as described elsewhere [12].
The kDNA PCR products of clinical samples, Mexican isolates and reference strains, were Southern or dot blotted onto nylon membranes and were hybridized with the cloned fragments of kDNA used as probes: B4Rsa, which hybridizes specifically to members of the L. donovani complex; 9.2 and 9.3, specific for the L. mexicana complex; and B18, specific for members of the L. braziliensis complex. The probes were labeled with DIG Random Primer DNA labeling kit (Boehringer Mannheim) and either visualized colorimetrically with NBT and BCIP (Boehringer Mannheim) or labeled with [32P]d ATP, using the Prime-it™ Random Primer DNA labeling kit (Stratagene). The hybridization conditions were described elsewhere [14, 17].
Patients diagnosed with CL accepted treatment with meglumine antimoniate (Glucantime®). Glucantime is marketed in 5 mL ampules containing 1.5 g of N-methyl-glucamine antimoniate, which corresponds to 425 mg of Sb51. Treatment consisted in one ampule by intramuscular injection per day until healing [19].
Primers DeB8 and AJS1, specific for the Leishmania (L.) subgenus [13], amplified the kDNA of L. (L.) mexicana Bel 21, L. (L.) mexicana M379, L. (L.) amazonensis PH8, L. (L.) amazonensis M2269, L. (L.) donovani DD8, L. (L.) infantum/chagasi PP75, 10 Mexican strains of Leishmania, and many clinical samples from patients with skin lesion from Campeche, Tabasco, Veracruz, and Quintana Roo (Tables 1 and 2, Figure 1) [17].
PCR with the primers M1 and M2 specific for the L. mexicana complex [14] resulted in the amplification of kDNA of L. (L.) amazonensis PH8 and M2269 with a band size of 700 bp and L. (L.) mexicana BEL21 with a band size of 800–820 bp. This difference can be used diagnostically to distinguish between L. (L.) amazonensis and L. (L.) mexicana isolates. The size of the kDNA amplicons of the Mexican strains is more similar to the size of the amplicons of L. (L.) amazonensis group than the amplicons of L. (L.) mexicana. Negative controls, T. cruzi and M. tuberculosis, did not amplify [17].
PCR specific for the L. braziliensis complex carried out with B1 and B2 primers [8] produced a kDNA amplification band of 750 bp of L. (V.) braziliensis LTB300, LC53, L. (V.) braziliensis M2903, L. (V.) braziliensis M2904, L. (V.) braziliensis reference strains, and some skin biopsies from Nayarit and several skin samples from Campeche state.
In order to have a more accurate identification of the Leishmania species in Nayarit, the skin biopsies were PCR analyzed with primers 3J1 and 3J2 specific for DNA genomic of L. (V.) braziliensis. Most of the samples amplified giving a band of 617 bp. The PCR products hybridized positively with the LbJ38 probe, which is species specific for L. braziliensis complex [18, 20].
PCR with specific primers D1 and D2 for the L. donovani complex resulted in the amplification of kDNA of the L. (L.) donovani DD8 and L. (L.) infantum/chagasi PP75 reference strains, and bone marrow and liver biopsy from a patient from Chiapas with VL were amplified [16, 21].
PCR products of the kDNA of Mexican strains of Leishmania mexicana and clinical samples amplified with primers AJS1 and DeB8, specific for the subgenus Leishmania, were dot blotted and tested with probe 9.2, specific for the L. mexicana complex. The probe hybridized with high affinity to L. (L.) mexicana BEL21, the 10 Mexican strains of Leishmania mexicana, several samples and biopsies from Campeche state, and DNA from a bone marrow aspirate, from a patient from Tabasco, with VL; kDNA from the reference strains other than L. mexicana that did not hybridize.
PCR products amplified with primers B1 and B2, specific for the L. braziliensis complex, were Southern blotted and tested with probe B18, specific for the L. braziliensis complex. This probe hybridized to L. (V.) braziliensis LTB300 and to DNA from skin biopsies from patients from Campeche and some from Nayarit states (Figure 1) [20].
PCR with specific primers for ITS1 resulted in the amplification of the Leishmania reference strains, the Mexican strains and isolates of L. mexicana, and the clinical samples from Campeche giving 300–350 bp amplification bands. Restriction of the ITS1 gene amplicons of L. (V.) panamensis, L. (V.) guyanensis, and L. (L.) braziliensis reference strains with the endonuclease HaeIII generated patterns with two bands of 170 and 150 bp; L. (L.) amazonensis generated two bands of 220 and 140 bp; and L. mexicana generated three bands of 200, 80, and 40 bp.
Most of the Mexican strains and isolates of Leishmania displayed a restriction pattern similar to that of L. (L.) mexicana reference strain; nine of these were obtained from LCL patients from Campeche. Some showed a mixed pattern compatible with L. (L.) mexicana and L. (V.) braziliensis; some others showed a mixed pattern compatible with L. (L.) amazonensis and L. (L.) mexicana (Table 2) [11].
In relation to the clinical samples from Campeche, most of them amplified a restriction pattern similar to the L. (L.) mexicana reference strain. In some samples, extra bands of 50 and 25 bp were observed, suggesting a coinfection, as it was found in a previous study with kDNA PCR analysis of clinical samples that DNA from both L. (L.) mexicana and L. (V.) braziliensis was identified (Table 2) [11, 15].
In Mexico since 1985, cases of LCL, DCL, MCL, and VL clinical expressions were reported in 15 states; the species involved were L. (L.) mexicana, L. (V.) braziliensis, and L. (L.) chagasi. LCL was the most common, and all cases were considered caused by L. (L.) mexicana [6, 22]. The five major foci of Leishmania transmission were in rain forest of southern Campeche, La Chontalpa (the cocoa-producing district of Tabasco), and the southern coffee producing of Nayarit, southern Quintana Roo, and Chiapas (Figure 1).
In Nayarit, state of the Pacific endemic region, LCL was recorded in Caleras de Cofrados since 1987 [22], a district near Tepic, the state capital city (Figure 1). The etiological agent was thought to be L. (L.) mexicana. In our studies using kDNA PCR and hybridization techniques, we have demonstrated that the L. braziliensis complex is present in Nayarit, and we were able to distinguish between two variants or two different species of L. (V.) braziliensis. We believe this was the first report of L. (V.) braziliensis in Nayarit, Mexico [20]. The population affected with skin lesion were 5–65 years old; males were the most affected and their main activity was the harvesting and/or growing coffee. The possible vectors are Lutzomyia cruciata, Lutzomyia diabolica, and Lutzomyia shannoni, which were captured and identified at the plantation. In relation with the animal reservoirs, no studies have been reported [20].
Biopsies, clinical samples, and isolates from LCL patients from several districts of Campeche state, mainly from Calakmul, were PCR amplified with specific primers for kDNA of L. braziliensis and L. mexicana complex members and primers specific for Mexican strains of L. mexicana [19] and also were analyzed by ITS1 PCR-RFLP [12]. We detected in Northern Calakmul 43 % of cases infected with L. mexicana, 25% of cases with L. braziliensis complex members, 62% of mixed infection of Mx L. mexicana + L. (L.) mexicana, and 25% of cases infected with L. braziliensis complex + L. (L.) mexicana. The most affected community of this area was La Mancolona, with a 6.5% of prevalence; this village is located 3–4 km away from the crops and is more urbanized due to deforestation (Figure 3a). The most affected population in this village were adult males (66%) [19].
In central Calakmul 15% of the cases were infected with L. (L.) mexicana, 25% of the cases infected with L. braziliensis complex members, and 37% of the cases infected with Mx L. mexicana L. (L.) mexicana. La Guadalupe village had the highest prevalence rate (2.2%) and children were the most affected (67%) [19].
In southern Calakmul 25% of the cases were infected with L. (L.) mexicana, 62% with L. braziliensis complex members, and 75% with both L. (L.) mexicana and L. braziliensis complex members. Dos Lagunas Sur was the most affected community, located close to the border with Belize, with 12% prevalence (Figure 2c). People in this village farm chili crops around their houses, which are located very close to the forest, and the population affected were children (50%), women, and men (50%) (Figures 2a–c and 3a–c) [19]. In relation to the vectors, L. mexicana infections in two sand fly species, Lu. shannoni and Lutzomyia ylephiletor, were found in Dos Lagunas Sur, whereas in La Mancolona, L. (L.) mexicana infections were found in Lu. shannoni, Lu. cruciata, Lu. o. olmeca, and Lu. Panamensis [23].
Patients from the endemic Gulf of Mexico region, with skin lesions suffering from cutaneous leishmaniasis.
Communities situated in the leishmaniasis endemic region of Gulf of Mexico. People in these villages farm chili crops around their houses, located very near the forest close to the border of Belize and Guatemala.
Regarding to the animal reservoirs, L. (L.) mexicana was identified in four species of wild rodents: the black-eared rice rat, Oryzomys melanotis; the hispid cotton-rat, Sigmodon hispidus; the big-eared climbing rat, Ototylomys phyllotis; and the Yucatan deer mouse, Peromyscus yucatanicus [24].
We found most of the cases of DCL in the states of Tabasco and Veracruz (Figure 1). These states have a common border in the endemic region of the Gulf of Mexico and are characteristically tropical rain forest, with considerable rainfall and important agricultural activities, including the production of cocoa, sugar cane, and rubber. We collected isolates from patients with DCL or LCL in these states and some from Campeche. Their DNA was amplified with primers M1 and M2 [17] specific for kDNA of L. mexicana complex. The size of PCR products (680–720 bp) of the Mexican isolates is more similar to the size of the PCR products (700 bp) of L. (L.) amazonensis group than the PCR products (800–820 bp) of L. (L.) mexicana BEL21. The isolate PCR products hybridized with probe 9.2 specific for the L. mexicana complex. Their DNA was also analyzed using ITS1 PCR-RFLP, and we confirmed the presence of both DNA of L. (L.) amazonensis and L. (L.) mexicana in the same isolate (Table 2) [12, 17].
In Mexico, it has been reported that VL was caused by L. (L.) chagasi and confined to Central endemic region [22]. Subsequently, in the Pacific endemic region states of Chiapas, Guerrero VL was detected. In Tabasco, only cases of LCL and DCL caused by L. (L.) mexicana have previously been reported [25]. In our studies by kDNA analysis, we have found VL cases in Tabasco (a 6-month-old immunosuppressed male) [21] and in Chiapas (a 36-year-old male coinfected with HIV and Pneumocystis carinii) to be caused by L. (L.) mexicana [26]. These findings are important because it indicates that these species, typically cutaneous, can visceralize in immunocompromised patient, and in Mexico, MCL, LCL, and VL coexist in some endemic areas. This is the first case reported in Mexico of coinfection by L. (L.) mexicana and HIV, which was manifested as VL. Our results agree with those found in Hernandez [26], who reported in Venezuelan patient displaying the symptoms of VL, a coinfection with HIV and a Leishmania variant strain sharing kDNA sequences with L. braziliensis and L. mexicana [27].
Treatment of CL patients with Glucantime® was successful in 96% of cases, regardless of the number and location of lesions. To obtain complete healing of lesions, the doses needed were in children from 2 to 20 and in adults from 2 to 67 ampules, although some patients cure spontaneously [19].
In the endemic areas evaluated in the present studies, the risk factors associated with CL were identified as the human colonization of large areas of previously untouched rain forests, where CL is endemic. The urbanization and deforestation are important factors because the Leishmania transmission cycles are adapting to peridomestic environments and are spreading to previously no endemic areas with domestic animals as potential reservoirs and spending nocturnal periods in the forest for cultivation of agricultural crops (e.g., chili and coffee) (Figure 3a–d) [11, 19, 20].
In conclusion, our findings are interesting because we have shown that in the typical endemic regions of Gulf of Mexico and Ocean Pacific of Mexico, CL can be caused by several species of the L. mexicana and L. braziliensis complexes and in some clinical samples, we found DNA of both complexes. Furthermore, we found DCL caused by a mix infection with strains of L. (L.) amazonensis and L. (L.) mexicana [12], both belonging to the L. mexicana complex. VL can be caused by L. (L.) chagasi and in immunocompromised patients by L. (L.) mexicana. Diagnosis of leishmaniasis by PCR and hybridization of kDNA and ITS1 PCR-RFLP analysis of Leishmania DNA must be combined for the reliable characterization of Leishmania species mainly in endemic areas where the presence of multiple species of Leishmania overlap clinical pictures demands simultaneous species identification [12]. In Mexico, the geographic range in which CL is endemic has increased in size due to urbanization, new settlements, and ecological, social, and educative conditions, which favors its permanence and transmission, as it has occurred in Calakmul.
Financial support for this research was provided by Secretaría de Investigacion y Posgrado, Instituto Politecnico Nacional, Mexico, and Conacyt. Amalia Monroy-Ostria is a fellow of COFAA, Instituto Politecnico Nacional, Mexico. We thank Erik Fabila-Monroy, MBA, for reviewing the English of the manuscript.
So far, the pathogenesis of neuroinflammatory diseases, including multiple sclerosis (MS), epilepsy, Parkinson’s disease (PD), Alzheimer’s disease (AD), etc., is still unclear, of which therapeutic effects are not satisfactory, bringing great challenges to public health care. The pathological processes of these diseases are often accompanied by the production of neuroinflammation that cause a series of bad effects such as firing pro-inflammatory signaling pathways and even neuron pyroptosis, as well as cell death. The accumulated data show that neuroinflammation is characterized by the activation of glial cells and production of inflammatory mediators in the central nervous system (CNS) and peripheral nervous system (PNS) [1].
\nActivated glial cells, triggering neuroinflammation, include Schwann cells as well as satellite glial cells in PNS and microglia, astrocytes, and oligodendrocytes in CNS [2]. Glial cells are of importance for critical responses to neurological diseases and injuries, including active tissue remodeling, phagocytosis, etc. [3].What’s more, glial cells often acting as double-edged swords not only evoke the neuronal damage but also promote tissue repair [4]. Under pathological conditions, microglial cells, as one kind of resident immune cells in CNS [5], could secrete a large number of cellular inflammatory factors, increase oxidative stress of neurons, and induce apoptosis or pyroptosis of neurons. At the same time, M2 microglia secrete various neurotrophic factors and anti-inflammatory factors such as IL-4 and IL-3, which play a neuroprotective role in cerebral ischemia and hypoxia [6, 7].
\nAstrocytes are widely distributed in the nervous system, showing its function by providing nutrition and support to adjoining neurons [8]. Therefore, the excitability of neurons could be regulated by the neurotransmitters secreted from astrocytes. At the same time, it could synthesize and release a variety of immune factors to participate in the neuronal immune response. Oligodendrocytes are the unique neuroglial cells that form the myelin sheath, which is the key structure for neurons to propagate APs. CNS myelin hypoplasia or demyelinating changes are the pathogenic factors of neuroinflammatory diseases [9].
\nIn the mid-twentieth century, after the discovery of AP, Hodgkin and Huxley, who firstly proposed the concept of ion channels, record sodium currents by using voltage clamp technology [10, 11]. Traditionally, glial cells were considered as non-excitatory cells, but with the development of research in this field, sodium channels have been found also to play crucial roles in physiological and pathological function of these cells [12, 13].
\nThe activation of sodium channel is triggered by membrane depolarization, which produces transient sodium current and AP [14]. In neurons, sodium channels are composed of a single α-subunit, which forms ion-selective and voltage-sensitive pores, and one or two auxiliary β-subunits, which seems to affect channel gating and expression [15].
\nThese channels drive electrical generation in neurons (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8), muscle cells (Nav1.4), and myocardial cells (Nav1.5). The typical role of Nav channels has been widely studied [16]. The dysfunction of sodium channels could result in neurological diseases, including neuropathic pain [17, 18, 19], peripheral neuropathy [20], epilepsy [21], and MS [22, 23].
\nHowever, the dysfunction of glial VGSCs is seemingly not related to abnormal excitation of neurons, but of importance in the astrogliosis and M1 polarization of microglia, which could induce refractory neuroinflammatory diseases. Glial sodium channels are closely related to phagocytosis, secretion of cytokines (IL-α, TNF-α), and migration. Then, glial cells are activated after tissue damage or disturbance, accompanied by morphological changes, enhanced migration, phagocytosis, secretion of inflammatory molecules (such as cytokines and nitric oxide), and antigen presentation [24].
\nAlthough glial cells do not produce AP under physiological conditions, they can show excitability through ion flux, especially in the form of [Ca2+]i oscillation. Ca2+ kinetics is involved in microglial activation and regulation of many effector functions, including cell migration [25, 26] and release of chemokines/cytokines and nitric oxide [27].
\nThe Na+/Ca2+ exchanger (NCX) operates in a forward mode, transmits Na+ ions down the concentration gradient to the cell, and then returns to output Ca2+, or if the electrochemical gradient of Na+ decreases or the cell depolarizes, the operation realizes the reverse mode by outputting Na+ ions in exchange for Ca2+ [28]. Therefore, sodium channel activity has the ability to increase [Ca2+]i through the reverse mode of NCX.
\nThe research shows that Nav1.6 can generate continuous sodium current [29], drive the reverse operation of NCX, and generate the inlet. Ca2+ enters the cytoplasm. In this respect, like all eukaryotic cells, the intracellular free Ca2+ level is strictly regulated, which is crucial in the signal transduction pathway of microglia. Studies have shown that Nav1.1 and Nav1.6 were persistently reduced during epileptogenesis [30]. Under the MS pathological condition, the results showed that the removal of Nav1.5 from astrocytes could significantly worsen the clinical outcome of experimental autoimmune encephalomyelitis (EAE) [31] and the sodium channel Nav1.2 is expressed by scar and reactive astrocytes in plaque [32]. Studies have shown that under PD pathological conditions, Nav1.1 [33] in hippocampal astrocytes is significantly increased, and Nav1.6 is highly expressed in activated microglia [34].
\nThere is a close relationship between the structure and the function of sodium channels (Figure 1). Therefore, in this chapter, we aim to describe the physiological and pathological roles of VGSCs contributing to the activity of glial cells and discuss whether VGSC subtypes could be used as a novel drug target, with an eye toward therapeutic implications for neuroinflammatory diseases.
\nStructure of Nav channels. Schematic representation of Nav channel subunits. The Nav channel α subunit is often illustrated together with auxiliary subunits β1 and β2; extracellular domains of the β subunits are shown as immunoglobulin-like folds (shown in blue), interacting with the extracellular loops of α subunits. Roman numerals indicate the domains of the α subunit; segments 5 and 6 (shown in purple) are considered as pore-lining segments, and S4 helices (green) make up the voltage sensors. The yellow circle in the intracellular loop of domains III and IV represents the inactivation gating ball, IFM motif.
MS, a chronic inflammatory disease of the CNS, is characterized by demyelination, axonal injury, neuronal loss, and progressive inflammatory responses in the brain and spinal cord [35]. EAE is a classic model of MS, of which the pathological progress is very similar to MS. Under pathological conditions, glial cells (microglia, astrocytes, oligodendrocytes, glial stem cells) can act as regulators, effectors, and even targets of inflammatory response, not only causing tissue damage but also promoting tissue repair [4]. Glial cells are essential for critical responses to neurological diseases and injuries, including active tissue remodeling and phagocytosis [3]. Studies have shown that sodium channels are not only traditionally associated with the generation and transmission of neuronal APs, but also can be expressed in electrically inexcitable cell types including astrocytes [36, 37], oligodendrocyte precursor cells [38, 39, 40], Schwann cells [41], microglia [42, 43], and cancer cells [44, 45, 46]. The regulation of glial function by sodium channels is of special significance for the response of reactive glial to CNS diseases and insults [14].
\nMicroglial cells are the resident immune cells of the CNS. Under physiological conditions, microglial cells are usually highly branched cells with dynamic processes that can actively monitor the microenvironment of the CNS to protect nerve homeostasis [47]. However, under pathological conditions such as MS, microglia cells could be activated and recruited [48]. Microglial cells undergo significant immunophenotype and cellular and morphological plasticity in response to damage in the activation pathway [49]. The activation of microglial cells is related to the pathological conditions of the CNS. In addition, migration of microglial cells to damaged cells and pathogens plays an important role in microglial-mediated CNS injury and infection [50].
\nMicroglial cells activated in EAE and MS are widely distributed and promote disease processes through a variety of mechanisms, including inducing effector T cell proliferation [51], production of pro-inflammatory cytokines [52], and phagocytosis of myelin. Moreover, studies have found that microglial cells activated in newly formed MS lesions are thought to be the main cell type that triggers the neuroinflammatory cascade after oligodendrocyte apoptosis [53]. Increased intracellular calcium and subsequent stimulation of the signaling cascade have been shown to be central events in the regulation of the function of activated microglial cells [54]. Studies by Matthew et al. have demonstrated that activation of microglial cells as well as macrophages is accompanied by upregulation of sodium channel Nav1.6 in EAE and MS [13]. In both the Nav1.6 blocker model and the Nav1.6 knockout model, the extent of inflammatory infiltration in EAE and the phagocytosis of activated microglia cells were effectively reduced, thus confirming that Nav1.6 was a key contributor to the activation and pathophysiological function of microglial cells [13, 55].
\nIn another important pathological manifestation, migration of microglial cells to lesions of the CNS is a complex and highly coordinated process involving multiple intersecting cellular pathways such as membrane adhesion and retraction, cellular polarization, and receptors transducing external migratory signals [56]. One of the preliminary structural events in chemotaxis is the formation of membrane protrusions and high enrichment in the aggregated F-actin network [57]. In addition, actin-binding protein, calmodulin, and GTP-binding signaling protein Rac also are located at the protrusions [58, 59, 60]. The activity of MAP kinase and the reorganization of actin filament also play important roles in cell migration [61]. Importantly, Ca2+ signaling seems to have an effect on protrusions and movement [62], as intracellular Ca2+ levels can regulate cell migration, and the activity of a variety of migration-related effector molecules including Rac and MAP kinase is modulated by the levels of intracellular Ca2+ [63, 64, 65]. Studies support the contribution of the sodium channel Nav1.6 in a pathway that controls the extension of lamellipodial protrusion at the initial stage of cell migration [66, 67]. Sodium channels regulate Ca2+ transients in ATP-stimulated microglia and play a role in the activation of two key migrating proteins, Rac1 and ERK1/2 [48] (Figure 2).
\nNeuroglial Nav channels evoking Ca2+ signaling pathway. Schematic of putative cell signaling of Nav channel contribution to intracellular Ca2+ levels and downstream pathways. Depolarization of neuroglial membrane leads to activation of VGSCs (Nav) allowing influx of Na+. Increased [Na+]i causes reverse operation of NCX, which contribute to the level of Ca2+. The Ca2+ signaling initiates downstream effects on neuroglial cell functions.
In summary, Nav1.6 sodium channel is involved in the activation and functional regulation of microglia in EAE and MS and has potential value as a therapeutic target.
\nAstrocytes participate in ionic homeostasis, neuronal metabolic support, and the formation and maintenance of the blood–brain barrier in the normal CNS and react to form glial scars when injured [8]. With the deepening understanding of the importance of astrocytes in CNS pathology, it has been proven that astrocytes play a key immunoregulatory role in damaged CNS [68, 69, 70]. Though astrocytes have traditionally been considered to be electrically unexcitable, studies have demonstrated that these cells express VGSCs [71, 72], including the subtype Nav1.5 [73, 74]. It is worth noting that the expression of astrocyte sodium channels in rodents is not a static process, but a dynamic process that changes with the age of astrocytes, exposure to extracellular factors, and damage [75, 76]. The voltage-gated sodium channel Nav1.5 is less expressed in astrocytes in non-pathological human brain but shows a strong upregulation of Nav1.5 in both acute and chronic MS lesions [71].
\nDifferent from excitable neurons, astrocytes exhibit their excitability by mainly in the form of [Ca2+]i oscillations. Cytoplasmic Ca2+ levels in astrocytes come from multiple regions, including the endoplasmic reticulum [77], mitochondrial sodium-calcium exchange [78], and extracellular space [79]. The [Ca2+]i flux of astrocytes not only regulates neuronal synaptic transmission, but is also important for many steady-state cell functions, including migration and proliferation, of astrocytes [78, 80, 81]. An important mechanism by which [Ca2+]i is regulated in astrocytes is the reverse (Ca2+ import) activity of the NCX [82]. The positive pattern of NCX is to transport Na+ to the cell and then return Ca2+ to the cell [28]. When the Na+ electrochemical gradient is reduced or the cell depolarizes, NCX outputs Na + in exchange for Ca2+ by running in reverse mode [82, 83]. Therefore, sodium channel activity has the ability to increase [Ca2+]i through the reverse pattern of NCX [82]. Interestingly, mechanical strain injury increases intracellular Na+, causing NCX to operate in a reverse mode in cortical astrocytes, increasing the level of [Ca2+]i [84].
\nRecent studies have shown that Nav1.5 plays an important role in in vitro models of glial injury by triggering the reverse mode operation of the NCX [71, 74]. Laura et al. confirmed that in the conditional knockout Nav1.5 model in astrocytes, the absence of Nav1.5 leads to a significant deterioration in the clinical outcome of EAE and an increase in inflammatory infiltration [31]. While the previous studies of MS in vivo models have shown that a variety of voltage-gated sodium channel blockers, including phenytoin [85], lamotrigine [86], carbamazepine [85], and safinamide and flecainide (Nav1.5 blocker) [87], could improve the clinical status and axonal damage, this suggests that Nav1.5 and NCX may be potential targets for the treatment of MS by acting on [Ca2+]i to regulate astrocyte proliferation (Figure 2).
\nDuring the development of CNS, oligodendrocytes (NG2 cells) originating in different regions of the brain migrate to their destinations to participate in the development [88, 89]. The directed migration of these glial progenitor cells is critical not only for the formation of myelin in the developing brain, but also for the repair of myelin after injury [90, 91]. Although NG2 cells express VGSC, they only trigger transient depolarization and fail to produce typical APs [92, 93]. Studies have found that intracellular Na+ and Ca2+ levels, membrane depolarization, and migration ability of NG2 cells increased after the application of GABA [93]. While in the siRNA knockdown or blocking sodium channel model, the increasing tendency of [Na+]i and [Ca2+]i was significantly reduced, and cell migration was suppressed [93]. Moreover, a similar reduced [Ca2+]i and decreased cell migration were also shown in the NCX siRNA knockdown and blocker models [93].
\nIn general, GABA induced the depolarization of the NG2 cells and activated the sustained Na+ current, which reverted the activity of type I Na+/Ca2+ exchangers (NCX1) to evoke the increase of [Ca2+]i [93]. Significantly, further evidence suggests that this unique pathway is associated with NG2 cell migration [93, 94]. Therefore, the important role of non-inactivated Na+ channels and NCXs in the development and function of NG2 glial cells in the brain suggests its potential values in myelin repair.
\nEpilepsy is a kind of chronic brain dysfunction syndrome caused by abnormal firing of neurons, which has been listed as one of the five major neuropsychiatric diseases by the World Health Organization (WHO). At present, the number of epilepsy patients has reached 65 million worldwide [95], and especially the developing countries account for four fifths of this number [96], bringing serious economic burden to the patients’ families and their country.
\nThe previous studies on epilepsy were focused on clarifying the mechanisms of neuron dysfunction as well as neural network. In recent years, the researches on glial cells regulating neuron activity have surfaced with increasing frequency, which provide sufficient evidence for the involvement of glial cells in inducing epilepsy [95]. Glial hyperplasia is an important hallmark in the course of epilepsy; it refers to a spectrum of physicochemical and physiological changes in glial cells, particularly in astrocytes and microglia. The activation of astrocytes after epileptic seizure may be beneficial to the recovery of extracellular homeostasis [97]. However, more and more evidence proved that reactive glial cells could induce neuroinflammation by releasing the cytokines, chemokines, and other molecules, which is likely to cause neuron death, tissue damage, and microglial hyperplasia [98]. Unrestrained reactive gliosis might also cause hippocampal sclerosis, disturbing the normal physiological regulation function and promoting the epileptic seizure [99].
\nGlial cells express several types of ion channels. The Cl−, K+, H+, and Ca2+ channels have been found to express in microglia, and the Kir [100] and Na+ channels are highly expressed in astrocytes, which have been implicated in multiple functions of these cells [101]. These channels of different subtypes can be involved in regulating the membrane potential, migration, phagocytosis, intracellular ion concentration, and secretion of various cytokines and chemokines in glial cells [102].
\nGenetic studies have shown that the mutations associated with epilepsy mainly occur in genes encoding sodium channels [103]. VGSCs are a class of voltage-dependent ion channels that are highly expressed not only in excitable cells [104], but also in non-excited cells, such as astrocytes, oligodendrocytes, microglial cells, etc. [105]. Recently, it has been found that sodium channel plays an important role in the activation of glial cells and may become a new target for antiepileptic drugs.
\nNeuronal excitability is closely related to the movement of sodium or potassium across the extracellular space (ECS). Because of the narrow volume of this space, the extremely small fluxes could also evoke significant changes in anion concentration [95]. Normally, a single AP can increase the extracellular K+ concentration by nearly 1 mM. However, at the epileptic seizure period, the continuous neuron firing could raise the potassium concentration from the normal level ~3 mM to 12 mM [106]. In normal brain, neurons rapidly regulate K+ concentration to 3 mM through Na+/K+ ATPase, and Na+ activates Na+/K+ ATPase activity through VGSCs in astrocytes, providing an important feedback pathway for regulating K+ level in extracellular space and maintaining stability of the central nervous system [106].
\nThus far more and more reports have mentioned that sodium channel subtypes are widely distributed in most CNS glial cells [72, 107], including the TTX-S sodium channel Nav1.3 and Nav1.6 as well as TTX-R sodium channel Nav1.5 [14]. In the post-status epilepticus (SE) model induced by kainic acid (KA) intrahippocampal injection, the expression of Nav1.6 in ipsilateral hippocampal peaked at 21 days in astrocytes. On the contrary, there was no change in the expression of astrocyte Nav1.6 in the PTZ-induced epileptic seizure models, indicating that astrocyte Nav1.6 played a crucial role in promoting the epileptic process, but not in seizure period [108].
\nIt is known to all that the voltage-gated sodium channel is composed of one α subunit and two auxiliary β subunits [109]. Co-expressed with α subunits, β subunits could significantly increase the current density of sodium channels, which is partly due to the enhancement effects of β subunits on the expression of sodium channels [110]. In the chronic epilepsy model induced by electrical stimulation, sodium channel β1 subunits are colocalized with the reactive astrocytes, and the number of positive cells significantly enhanced a week after SE, so it is speculated that the β1 subunits could interact with extracellular matrix, promoting the network of intercellular synapses in the process of epilepsy [111].
\nMicroglia, as resident cells in the CNS, provide continuous immunosurveillance for the brain as well as the spinal cord [47]. When the body is invaded by exogenous substances, microglial cells respond to ATP or other cell signals, activated rapidly so as to provide immune defense. However, microglia cells can produce inflammatory factors in pathological conditions, causing damage to the body [49]. Microglial cells always express a large number of ion channels and surface receptors, which can induce relevant signaling pathways to convert extracellular changes into intracellular responses.
\nVGSCs are also distributed in microglial cells. Studies have shown that microglia not only express the TTX sensitivity sodium channels (Nav1.6 [13] and Nav1.1 [14]), but also express the Nav1.5 [14] (a TTX-resistant sodium channel) [14]. The blockade sodium channels of TTX and phenytoin could significantly weaken a variety of functions of activated microglia cells [12], such as the release of inflammatory cytokines [12, 102]. After a week of spontaneous epilepsy induced by electrical stimulation, the sodium channel subtypes were found to be highly expressed in microglial cells [112]. The Nax channel encoded by the SCN7A gene was observed to be significantly increased during the onset and development of epilepsy, and especially the high expression of Nax was detected in hippocampal sclerosis tissues from drug-resistant patients [113].
\nOcasepine, as a clinical drug that targeted on VGSCs, is often used to suppress the epileptic seizure clinically. This drug has been found that it could significantly reduce the number of activated astrocytes as well as microglial cells in the hippocampus CA1 region in cerebral ischemia model, which also reduce the neuron death in the hippocampus caused by ischemia [14]. It implies that sodium channels are involved in microglia activation, which could also promote the progression of neuroinflammatory disease, such as epileptogenesis.
\nAD is the most common progressive neurodegenerative disease, which is characterized by dystrophic neurites, neurofibrillary tangles, brain atrophy amyloid plaques, and loss of neurons and synapses [114]. In addition, AD is the cause of dementia and seriously affects the quality of life of the elderly [115]. Accumulated data show that the genetic mechanism of AD is mainly the accumulation of Aβ peptides and their aggregation in and deposition in amyloid plaques [116, 117]. The human genetics of familial AD also suggested that excessive production of amyloidogenic Aβ is a cause of early-onset AD; mutations in amyloid precursor protein (APP) or in its processing enzyme result in increased β-site cleavage of APP or favored production of longer, aggregation-prone variants of Aβ peptide [118]. In recent years, however, many studies found that microglia play an important role in the pathogenesis of AD. The reactive gliosis of AD histopathology revealed the abnormal morphology and proliferation of microglia [119, 120]. Several reports have linked microglia dysfunctions to AD, by showing microglial motility impairment in AD mice models [121]. Recently, it was recognized that microglia express voltage-gated ion channels, including Nav1.1, Nav1.5, and Nav1.6 [122, 123]. Furthermore, pharmacological block of the sodium channels has been attempted as a symptomatic treatment of epileptic features often associated with AD, as well as a relief to detrimental behavioral and psychological symptoms of dementia [124]. An interesting debate is if sodium channel activators could just be enough to compensate microglial dysfunctions to altered physiological properties of dysfunctional neuronal networks in AD patients [125].
\nPD is the second most common age-related disabling neurodegenerative disorder, estimated to affect over 10 million people worldwide, which PD presents clinically as bradykinesia, muscular rigidity, arresting tremor, and postural stability [126, 127, 128]. In addition, PD is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. The potential causes of PD remain uncertain, but recent studies suggest neuroinflammation and microglia activation play important roles in PD pathogenesis [129, 130]. However, persistent activation of microglia can mediate neuronal death and neurodegeneration by increasing the secretion of inflammatory molecules and cytokines, including tumor necrosis factor alpha (TNF-α) and reactive oxygen species (ROS) [131, 132]. Microglia express a number of ion channels, including sodium channels that regulate various aspects of inflammatory process, providing a potential target for intervention [14, 133]. Several studies demonstrated that VGSC can regulate a number of cellular functions such as morphological transformation, migration, and phagocytosis of microglia [12, 35]. This also indicates the well potential immunomodulatory properties of VGSC. 6-Hydroxydopamine (6-OHDA)-induced PD rat model found that the expressions of Nav1.1, Nav1.3, and Nav1.6 in the hippocampus were dynamically increased at different time points after dopamine depletion. Furthermore, cognitive deficits were effectively improved by phenytoin (sodium channel blocker) that has inhibitory effects on VGSCs in the brain [33]. Other study suggested that zonisamide, targeting VGSCs, may reduce neuroinflammation through the downregulation of microglial Nav 1.6 [134]. Those studies may contribute to its reported neuroprotective role in preclinical models of PD.
\nElectrophysiological patch clamp is a classic technique for traditionally recording neuronal sodium channels. Neuroglial cells are non-excitable cells, of which the cell membrane depolarization is not obvious. The bioproperties of neuroglial sodium channels evoked by high voltage in patch clamp recordings might be different from the actual situation in vivo. Therefore, this method has certain limitations in the process of studying neuroglial cells. With the development of ion probes, especially the recent discovery of visible light sodium ion probes as well as calcium ion probes, which could provide more intuitive results (such as higher resolution, better observation) for the functional study of glial cell Nav channels and Nav-NCX complexes [14]. The combined use of ion probes and patch clamping will make the experimental results both more abundant and accurate.
\nIn addition, the invention of the miniature two-photon microscope in 2017 [135] provided a powerful means for the functional research of nerve cells as well as glial cells. During studying brain activities and the development of neuroinflammatory diseases, glial cells could be labeled by GCaMP6 or dTomato to explore the function of the glial Nav-NCX complex. Two-photon imaging combined with EEG could not only explain the relationship between glial cell activity and EEG frequency more effectively, but also elucidate the important role of glial cells in neurological disorders, such as epilepsy. By using the miniature two-photon microscope, the conditional knockout mice could be applied to study the role of glial sodium channels in regulating the function of glial cells or the interaction between glial cells and neurons, including pruning of neuron synapses by microglial cells or regulating the neuroexcitability in vivo.
\nIn view of the central role of glia in CNS health and disease, it is necessary to further understand the physiological correlation of glial sodium channels and characterize the molecular pathways that control the function of sodium channels in these cells. There has been much work performed in cell culture, but further in vivo studies are of crucial importance for determination of the therapeutic implications of targeting glial sodium channels in neurological disorders. Therefore, novel neuroimaging techniques are of importance for studying the roles of neuroglial sodium channels in neuroinflammatory diseases. Meanwhile, with the heightened focus on developing sodium channel specific blockers, it is increasingly relevant to assess the roles of individual sodium channel isoforms in neuroglia cells (e.g., Nav1.6 in microglial cells, Nav1.5 in astrocytes). Further understanding of the signaling cascade linking sodium channel activity to glial effector function will facilitate the development of specific therapeutic targets for neurological diseases.
\nThis chapter was supported by National Natural Science Foundation of China (Nos. 81603410 and 81903995), Youth Talent Promotion Project of China Association of Chinese Medicine (No. CACM-2019-QNRC2-C10), Shanghai Municipal Commission of Health and Family Planning Fund (Nos. 20184Y0086 and 2018JQ003), Project for Capacity Promotion of Putuo District Clinical Special Disease (2019tszb02), Science and Technology Innovation Project of Putuo District Health System (Nos. ptkwws201902 and ptkwws201908), Project within the Budget of Shanghai University of Traditional Chinese Medicine (Nos. 18-DX-06 and 2019LK040), the Key Speciality Program (No. 2016102A), and Research Project (Nos. 2016208A, 2018302, 2018314, and 2018313) of Putuo Hospital, Shanghai University of Traditional Chinese Medicine.
\nThe authors confirm that this article content has no conflict of interest.
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