Phenytoin delays ischemic depolarization, but cannot block its long-term consequences, in the rat hippocampal slice.
The anticonvulsant phenytoin has been reported to block anoxia-induced losses of synaptic activity in the rat hippocampal slice and experimental ischemia-induced losses of synaptic activity in the guinea pig hippocampal slice. We examined phenytoin in our rat hippocampal slice model of experimental ischemia (anoxia +2 mM D-glucose). In this model, ischemic depolarization (ID) occurs 4-5 min after the introduction of anoxic medium, and oxygen and D-glucose are restored 1 min after the onset of ID. In control slices, synaptic recovery is never observed following ID in 2 mM D-glucose. Phenytoin (30,100 and 300 microM), perfused for 20 min prior to, and for 10 min following anoxia, did not allow for synaptic recovery following ID. At the higher concentrations, however, it did increase the latency to ID. In addition, the presynaptic volley (PV), which normally disappears at the time of ID, was lost substantially earlier in the presence of phenytoin. These findings suggest that the anti-ischemic effects of phenytoin reported by others are due to delay of ID. This may suggest that phenytoin will be effective in preventing global ischemia-induced damage only when the ischemic insult is of short duration.
Watson
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GB
Neurological Diseases Research, Searle Research and Development, Skokie, IL 60077, USA.
Lanthorn
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TH
D000818:Animals; D002545:Brain Ischemia; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects*; D000860:Hypoxia; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D010672:Phenytoin; D005947:Glucose