Pharmacological evidence for a correlation between hippocampal CA1 cell damage and hyperlocomotion following global cerebral ischemia in gerbils.
Global ischemia, induced in Mongolian gerbils by bilateral occlusion of the carotid arteries for 5 min, produced a significant increase in locomotor activity at 1 day post-occlusion and a severe loss of hippocampal CA1 neurons at 4 days post-occlusion. To explore the pharmacological relationship between ischemia-induced hypermotility and CA1 cell death in the hippocampus, we evaluated the efficacy of diverse classes of putative neuroprotective agents for preventing hypermotility and delayed neuronal death. Administration of any drug 30 min before global ischemia dose-dependently, and with similar potency, ameliorated both hippocampal delayed neuronal death and locomotor hyperactivity, with a rank order: tacrolimus (FK506)>nizofenone>clonindine>dizocilpine (MK-801)>6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione hydrochloride (YM90K)>phencyclidine>pentobarbital>2-(4-(p-fluorobenzoyl)-piperidin-1-yl)-2'-acetonaphthone hydrochloride (E-2001)>cis-(+/-)-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755)>3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U-50,488H)>piroxicam>eliprodil>vinpocetine. Furthermore, potencies of the protective effect on delayed neuronal death and inhibitory effects on hypermotility were closely correlated (r=0.98). These results suggest that post-ischemic CA1 injury and hypermotility share common mechanisms, and further imply that it is possible to predict the neuroprotective efficacy of drugs more easily by examining the inhibitory effects on post-ischemic hypermotility in global ischemia model in gerbils.
Katsuta
Kiyotaka
K
Department of Neuroscience, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa, Osaka 532-8514, Japan.
Umemura
Kazuo
K
Ueyama
Noriko
N
Matsuoka
Nobuya
N
D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006948:Hyperkinesis / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
D018696:Neuroprotective Agents