[Ion channels and demyelination: basis of a treatment of experimental autoimmune encephalomyelitis (EAE) by potassium channel blockers].
Voltage-gated potassium channels (Kv channels) are ion channels, openings of which provide an outward flow of potassium ions repolarising the cell. In neurons, Kv channels play a crucial role in action potential repolarisation and in shaping neuronal excitability. In non-excitable cells, such as T lymphocytes, Kv channels and calcium-activated K+ channels (KCa channels) determine the driving force for Ca2+ entry. During T cell activation the calcium entry depolarises the cell and increases the cytosolic calcium concentration, which in return activates Kv and KCa channels. K+ channel opening repolarises the cell and drives the membrane potential to a negative voltage. The roles of Kv channels in nervous and immune systems have been investigated here by means of a rat experimental autoimmune disease of the central nervous system, the experimental autoimmune encephalomyelitis (EAE). EAE is characterised clinically by paralysis, and pathologically by inflammatory cell infiltrations into the brain and the spinal cord. Among the inflammatory cells, T lymphocytes play a major role. Hence, EAE can be adoptively transferred into syngenic animals by the injection of T cells reactive to myelin antigens. During adoptive-EAE, somato-sensory evoked potentials recorded along the spinal tracts decrease in amplitude and axonal propagation is disrupted. We have analysed the consequences of Kv channels blockade by peptidyl toxins on central nerve conduction, on T cell activation and on the time course of EAE. In rat optic nerves, Kv channels have been identified up from postnatal day 1. Their blockade by kaliotoxin (a scorpion toxin) or by dendrotoxin-I (a snake toxin) enlarges the compound action potentials, demonstrating the participation of Kv channels to spike repolarisation. This effect disappears at adult age due to the sequestration of Kv channels under the myelin, in the paranodal regions. During acute demyelination by lysophosphatidyl-choline, the surface area of compound action potential decreased probably because conduction block occurred. Demyelination unmasked Kv channels, which are again accessible to toxins. Their blockade by dendrotoxin-I or kaliotoxin favoured a slow delayed conduction suggesting that those Kv channel blockers exert a neurological benefit during demyelinating diseases. In a T-cell line reactive to myelin basic protein antigen, which is used to adoptively transfer experimental autoimmune encephalomyelitis, Kv1.3 channels are constitutively expressed. Their blockade leads to a pronounced reduction of the T cell proliferative response, cytokine production and Ca2+ influx. In the rat, blockade of Kv1.3 inhibits the delayed type hypersensitivity response to myelin basic protein prevents and treats adoptive experimental autoimmune encephalomyelitis. Blockade of Kv channels alone or in combination with KCa channels improves the symptoms of the disease. These results demonstrate that K+ channel blockers displaying high selectivity are potent immunosuppressive agents with beneficial symptomatic effects in experimental autoimmune encephalomyelitis.
Laboratoire Intégration des Informations Sensorielles, CNRS UMR 6150, Université de la Méditerranée, Faculté de Médecine, IFR Jean Roche, Bd Pierre Dramard, 13916, Marseille, France.
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Devaux
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Beeton
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Béraud
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Crest
D000200:Action Potentials / Q000187:drug effects; D019264:Adoptive Transfer; D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000473:pathology*; D004546:Elapid Venoms / Q000633:toxicity; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D004676:Myelin Basic Protein / Q000276:immunology; D009186:Myelin Sheath / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity; D009900:Optic Nerve / Q000473:pathology; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012604:Scorpion Venoms / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects
D016207:Cytokines; D004546:Elapid Venoms; D007473:Ion Channels; D004676:Myelin Basic Protein; D009498:Neurotoxins; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; C108582:dendrotoxin I; C072276:kaliotoxin; D002118:Calcium