Global ischemic neuronal damage relates to behavioural deficits: a pharmacological approach.
Global cerebral ischemia leads morphologically to selective neuronal damage in the CA1 sector of the hippocampus and in the striatum and functionally to a deficit in spatial learning and memory in the water maze. The results of earlier studies which examined the relationship between neuronal damage and the deficits in the water maze were not clear cut. It has been observed, however, that neuroprotection reduces both the deficits in the water maze as well as the neuronal damage. The present study therefore approached the relationship between the neuronal damage and the deficits in water maze using pharmacological means. Global cerebral ischemia was induced in male Wistar rats by four-vessel occlusion for 20 min. Ischemic rats were treated with the N-methyl-D-aspartate receptor antagonist dextromethorphan, 50 mg/kg, with the calcium antagonist levemopamil, 30 mg/kg, with the radical scavenger EPC-K1, 10 mg/kg, or with solvent. Treatment with dextromethorphan or levemopamil reduced the deficit in spatial learning by limiting the increase in swim distance due to ischemia. Both substances also reduced the deficit in spatial memory by minimizing the ischemia-induced reduction in time spent in the quadrant of the former platform position during the probe trial. EPC-K1 had no influence on the ischemia-induced behavioural changes. Group comparisons demonstrated that the swim speed and the percentage of the swimming path along the sidewall were affected neither by ischemia nor by any of the treatments. Histological examination revealed neuronal damage in the hippocampus and in the striatum in all of the ischemic rats. Treatment with dextromethorphan or levemopamil reduced the hippocampal damage by 32% and 36%, respectively. In addition, dextromethorphan diminished the striatal damage about 78%. Correlation analysis demonstrated a correlation between the cumulative swim distance of all 20 escape trials and hippocampal damage (r = 0.65, P < 0.001) but not between swim distance and striatal damage (r = 0.14, P = 0.364). No correlation was found between quadrant time of the probe trial and either hippocampal damage (r = -0.21, P = 0.19) or striatal damage (r = -0.02, P = 0.889). The average percentage of the swimming path along the side wall related to the hippocampal damage (r = 0.28, P = 0.035) but not to the striatal damage (r = 0.05, P = 0.381). With respect to the average swim speed a correlation to striatal damage was observed (r = -0.69, P < 0.001) but not to hippocampal damage (r = -0.15, P = 0.168). These results clearly demonstrate that using the pharmacological approach it is possible to uncover certain correlations between functional deficits in the water maze and neuronal damage which are both due to global cerebral ischemia.
Block
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Max-Planck-Institute for Experimental Medicine, Göttingen, Germany.
Schwarz
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D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology* / Q000523:psychology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003915:Dextromethorphan / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014700:Verapamil / Q000031:analogs & derivatives / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology
D000975:Antioxidants; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D014810:Vitamin E; C066638:potassium ascorbyl tocopheryl phosphate; D003915:Dextromethorphan; D014700:Verapamil; C052752:emopamil; D001205:Ascorbic Acid