Cerebral ischemia in the Mongolian gerbil: (1) a model suitable for drug evaluation, (2) the role of convulsion and (3) cerebral blood volume changes
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Description
The occlusion of both carotid arteries in the gerbil produces near total cerebral ischemia because of absence of the posterior communicating arteries, and hence collateral blood supply from the vertebro-basilar system. Gerbils were anesthetized with a variety of agents and subjected to bilateral carotid arterial occlusion for 5-60 min. A sharp increase in the mortality rate was observed after 50 min of carotid occlusion. The mortality rate after 60 min of bilateral carotid occlusion was 100%. A low mortality rate (0-7%) was found after 50 min of occlusion when gerbils which weighed 45-55 gm were employed A standard model of cerebral ischemia was developed using gerbils weighing 45-55 gm and pentobarbital 60 mg/kg as the anesthetic agent. The gerbils were subjected to either 50 or 60 min of bilateral carotid arterial occlusion. Following the release of the carotid occlusion a single i.p. administration of saline or a test drug was performed. The gerbils were allowed to recover, and the post-ischemic mortality rate was determined. A reduction in the mortality rate after 60 min of carotid occlusion indicated a beneficial drug effect. An increase in the mortality rate after 50 min of carotid occlusion indicated an adverse drug effect The mortality rates after carotid occlusion and drug administration were compared to the mortality rates of the saline-treated gerbils using a non-parametric method for the analysis of small groups, Fisher's Exact Test. A significant decrease in the mortality rate after 60 min of carotid occlusion was observed after the administration of isoproterenol HCl 50 (mu)g/kg, amphetamine sulfate 5 mg/kg, methylprednisolone sodium succinate 35 mg/kg, and physostigmine HCl 0.25 mg/kg. A significant increase in the mortality rate after 50 min of carotid occlusion was observed after the administration of atropine sulfate 1 mg/kg, thiosemicarbazide 4 mg/kg, phenytoin sodium 50 mg/kg, aminooxyacetic acid 100 mg/kg, and theophylline 50 mg/kg The beneficial effects of isoproterenol and amphetamine were evaluated with additional studies to determine the dose-response relationship. The reduction in the post-ischemic mortality rate which was observed with both agents was correlated with the increase in heart rate and arterial blood pressure which they produced. The presumptive increase in cerebral blood flow which occurred after the administration of these two agents was credited for the improved post-ischemic mortality rate which was observed A reduction in the cerebral blood volume (CBV) after cerebral ischemia was observed with a method for the quantitative determination of cerebral blood volume employing a vascular infusion of trypan blue. The CBV was not decreased immediately after cerebral ischemia when ('131)I-RISA was administered i.p. or i.v. as an intravascular tracer. The difference in results was attributed to differences in the methods for determining the CBV. The presence of regions of post-ischemic hyperemia were felt to be obscuring a decreased CBV following cerebral ischemia as determined by the methods employing RISA A significant reduction in CBV was observed immediately after cerebral ischemia in gerbils which were treated with trimethadione and phenobarbital. The CBV was not reduced following cerebral ischemia and administration of phenytoin. Trimethadione and phenobarbital were also found to be more effective in reducing the mortality rate after 60 min of carotid occlusion than any of the agents which had been evaluated initially. The efficacy of several anticonvulsants in reducing the mortality rate after carotid occlusion was correlated with their efficacy in preventing convulsions in gerbils after the administration of pentylenetetrazol