Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels
The development of neuroprotective and repair strategies for treating progressive multiple sclerosis (MS) requires new insights into axonal injury. 4-aminopyridine (4-AP), a blocker of voltage-gated K+ (Kv) channels, is used in symptomatic treatment of progressive MS, but the underlying mechanism re...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-10-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00344/full |
| _version_ | 1811258934286090240 |
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| author | Peter Jukkola Yuanzheng Gu Amy E. Lovett-Racke Chen Gu Chen Gu |
| author_facet | Peter Jukkola Yuanzheng Gu Amy E. Lovett-Racke Chen Gu Chen Gu |
| author_sort | Peter Jukkola |
| collection | DOAJ |
| description | The development of neuroprotective and repair strategies for treating progressive multiple sclerosis (MS) requires new insights into axonal injury. 4-aminopyridine (4-AP), a blocker of voltage-gated K+ (Kv) channels, is used in symptomatic treatment of progressive MS, but the underlying mechanism remains unclear. Here we report that deleting Kv3.1—the channel with the highest 4-AP sensitivity—reduces clinical signs in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In Kv3.1 knockout (KO) mice, EAE lesions in sensory and motor tracts of spinal cord were markedly reduced, and radial astroglia were activated with increased expression of brain derived neurotrophic factor (BDNF). Kv3.3/Kv3.1 and activated BDNF receptors were upregulated in demyelinating axons in EAE and MS lesions. In spinal cord myelin coculture, BDNF treatment promoted myelination, and neuronal firing via altering channel expression. Therefore, suppressing Kv3.1 alters neural circuit activity, which may enhance BNDF signaling and hence protect axons from inflammatory insults. |
| first_indexed | 2024-04-12T18:22:55Z |
| format | Article |
| id | doaj.art-b09ef1de479145ac9b07725f173ee29e |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-12T18:22:55Z |
| publishDate | 2017-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-b09ef1de479145ac9b07725f173ee29e2022-12-22T03:21:22ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-10-011010.3389/fnmol.2017.00344301360Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 ChannelsPeter Jukkola0Yuanzheng Gu1Amy E. Lovett-Racke2Chen Gu3Chen Gu4Biomedical Sciences Graduate Program, Wexner Medical Center, The Ohio State University, Columbus, OH, United StatesDepartment of Biological Chemistry and Pharmacology, Wexner Medical Center, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, OH, United StatesBiomedical Sciences Graduate Program, Wexner Medical Center, The Ohio State University, Columbus, OH, United StatesDepartment of Biological Chemistry and Pharmacology, Wexner Medical Center, The Ohio State University, Columbus, OH, United StatesThe development of neuroprotective and repair strategies for treating progressive multiple sclerosis (MS) requires new insights into axonal injury. 4-aminopyridine (4-AP), a blocker of voltage-gated K+ (Kv) channels, is used in symptomatic treatment of progressive MS, but the underlying mechanism remains unclear. Here we report that deleting Kv3.1—the channel with the highest 4-AP sensitivity—reduces clinical signs in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In Kv3.1 knockout (KO) mice, EAE lesions in sensory and motor tracts of spinal cord were markedly reduced, and radial astroglia were activated with increased expression of brain derived neurotrophic factor (BDNF). Kv3.3/Kv3.1 and activated BDNF receptors were upregulated in demyelinating axons in EAE and MS lesions. In spinal cord myelin coculture, BDNF treatment promoted myelination, and neuronal firing via altering channel expression. Therefore, suppressing Kv3.1 alters neural circuit activity, which may enhance BNDF signaling and hence protect axons from inflammatory insults.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00344/fullvoltage-gated K+ channelmultiple sclerosis4-aminopyridineexperimental autoimmune encephalomyelitisradial astrogliabrain derived neurotrophic factor |
| spellingShingle | Peter Jukkola Yuanzheng Gu Amy E. Lovett-Racke Chen Gu Chen Gu Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels Frontiers in Molecular Neuroscience voltage-gated K+ channel multiple sclerosis 4-aminopyridine experimental autoimmune encephalomyelitis radial astroglia brain derived neurotrophic factor |
| title | Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels |
| title_full | Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels |
| title_fullStr | Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels |
| title_full_unstemmed | Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels |
| title_short | Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels |
| title_sort | suppression of inflammatory demyelinaton and axon degeneration through inhibiting kv3 channels |
| topic | voltage-gated K+ channel multiple sclerosis 4-aminopyridine experimental autoimmune encephalomyelitis radial astroglia brain derived neurotrophic factor |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00344/full |
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