CORRELATION BETWEEN ELECTROPHYSIOLOGICAL EFFECTS OF MEXILETINE AND ISCHEMIC PROTECTION IN CENTRAL-NERVOUS-SYSTEM WHITE-MATTER

Protection of CNS white matter tracts in brain and spinal cord is esse ntial for maximizing clinical recovery from disorders such as stroke o r spinal cord injury. Central myelinated axons are damaged by anoxia/i schemia in a Ca2+-dependent manner. Leakage of Na+ into the axoplasm t hrough Na+ channels causes Ca2+ overload mainly by reverse Na+-Ca2+ ex change. Na+ channel blockers have thus been shown to be protective in an in vitro anoxic rat optic nerve model. Mexiletine (10 mu M-1 mM), a n antiarrhythmic and use-dependent Na+ channel blocker, was also signi ficantly protective, as measured by recovery of the compound action po tential after a 60 min anoxic exposure in vitro. More importantly, mex iletine (80 mg/kg, i.p.) also significantly protected optic nerves fro m injury in a model of in situ ischemia. This in situ model is more cl inically relevant as it addresses drug pharmacokinetics, toxicity and CNS penetration. Optic nerve recovery cycles (defined as shifts in lat ency of compound action potentials with paired stimulation) were used to measure the concentration of mexiletine in optic nerves after syste mic administration, estimated at approximate to 42 mu M 1 h after a si ngle dose of 80 mg/kg, i.p. These results indicate that mexiletine is able to penetrate into the CNS at concentrations sufficient to confer significant protection. Na+ channel blockers such as mexiletine may pr ove to be effective clinical therapeutic agents for protecting CNS whi te matter tracts against anoxic/ischemic injury.