Forebrain ischemia: effect on pharmacologically induced seizure thresholds in the rat

Seizures are common after severe cerebral ischemia. To examine the mechanisms underlying these seizures, we determined the impact of prior forebrain ischemia on the seizure thresholds of four convulsants with differing modes of action: lidocaine, pentylenetetrazol (PTZ), N-methyl-D-aspartate (NMDA), and picrotoxin. Anesthetized Sprague-Dawley rats were chronically instrumented with screw electrodes and vascular catheters, and then subjected to 10 min of forebrain ischemia, produced by carotid occlusion and hypotension (mean arterial pressure to 30 mmHg). Animals were then awakened. 6, 24 or 48 h later, groups of awake animals received intravenous infusions of the four drugs. The total dose of drug infused prior to either electrical seizures (lidocaine, PTZ, and picrotoxin) or tonic-clonic convulsions (all drugs) were noted. For each drug, a group of Sham animals (no ischemia) served as controls. There were markedly different patterns of changes in the convulsant thresholds for the drugs. For example, at 6 h post-ischemia, rats treated with lidocaine died before convulsing, while the threshold for PTZ increased by 86%. There was no change in the picrotoxin threshold at 6 h, but the dose of NMDA needed to induce tonic-clonic seizure activity was reduced by 70%. By 48 h, lidocaine and PTZ thresholds had returned to values similar to those in Shams, but the NMDA threshold had now increased to a value 62% greater than Sham. Ten minutes of cerebral ischemia is followed by a complex and changing pattern of susceptibility to chemical convulsants. Finding suggests that early post-ischemic seizures may be related to increased NMDA receptor sensitivity.