The use-dependent sodium channel blocker mexiletine is neuroprotective against global ischemic injury

Mechanisms responsible for anoxic/ischemic cell death in mammalian CNS grey and white matter involve an increase in intracellular Ca2+, however the ro utes of Ca2+ entry appear to differ. In white matter, pathological Ca2+ inf lux largely occurs as a result of reversal of Na+-Ca2+ exchange, due to inc reased intracellular Na+ and membrane depolarization. Na+ channel blockade has therefore been logically and successfully employed to protect white mat ter from ischemic injury. In grey matter ischemia, it has been traditionall y presumed that activation of agonist (glutamate) operated and voltage depe ndent Ca2+ channels are the primary routes of Ca2+ entry. Less attention ha s been directed towards Na+-Ca2+ exchange and Na+ channel blockade as a pro tective strategy in grey matter. This study investigates mexiletine, a use- dependent sodium channel blocker known to provide significant ischemic neur oprotection to white matter, as a grey matter protectant. Pentobarbital (65 mg/kg) anesthetized, mechanically ventilated Sprague-Dawley rats were trea ted with mexiletine (80 mg/kg, i.p.). Then 25 min later the animals were su bjected to 10 min of bilateral carotid occlusion plus controlled hypotensio n to 50 Torr by temporary partial exsanguination. Animals were sacrificed w ith perfusion fixation after 7 days. Ischemic and normal neurons were count ed in standard H&E sections of hippocampal CA1 and the ratio of ischemic to total neurons calculated. Mexiletine pre-treatment reduced hippocampal dam age by approximately half when compared to control animals receiving saline alone (45 vs. 88% damage, respectively; P<0.001). These results suggest th at mexiletine (and perhaps other drugs of this class) can provide protectio n from ischemia to grey matter as well as white matter. (C) 2001 Elsevier S cience B.V. All rights reserved.