ZONISAMIDE AS A NEUROPROTECTIVE AGENT IN AN ADULT GERBIL MODEL OF GLOBAL FOREBRAIN ISCHEMIA - A HISTOLOGICAL, IN-VIVO MICRODIALYSIS AND BEHAVIORAL-STUDY

Brief periods of global cerebral ischemia are known to produce charact eristic patterns of neuronal injury both in human studies and in exper imental animal models. Ischemic damage to vulnerable areas such as the CA1 sector of the hippocampus is thought to result from excitotoxic a mino acid neurotransmission. The objective of this study was to determ ine the ability of a novel sodium channel blocking compound, zonisamid e, to reduce neuronal damage by preventing the ischemia-associated acc umulation of extracellular glutamate. Using gerbil model, animals were subjected to 5 min ischemic insults. Both pre- and post-ischemic drug administration (zonisamide 150 mg/kg) were studied. Histological brai n sections were prepared using a silver stain at 7 and 28 days post is chemia. The animals sacrificed at 28 days also underwent behavioral te sting using a modified Morris water maze. In vivo microdialysis was pe rformed on a separate group of animals in order to determine the patte rns of ischemia-induced glutamate accumulation in the CA1 sector of th e hippocampus. Pyramidal cell damage scores in the CA1 region of the h ippocampus were significantly reduced in animals pre-treated with zoni samide compared to saline-treated controls, both at 7 days (drug pre-t reated: 0.812 +/- 0.28, n = 8; controls: 1.625 +/- 0.24, n = 8; P < 0 .05) and 28 (drug pre-treated: 0.833 +/- 0.22, n = 12; controls: 1.955 +/- 0.26, n = 11; *P < 0.01) days post ischemia. However, animals re ceiving zonisamide post-treatment did not display significant differen ces from controls. Behavioral studies also showed significant preserva tion of function in drug-treated animals. Microdialysis studies confir med a reduction in glutamate release in drug-treated animals compared to saline-treated controls. Our data suggest that zonisamide is effect ive in reducing neuronal damage by a mechanism involving decreased isc hemia-induced extracellular glutamate accumulation and interruption of excitotoxic pathways. (C) 1997 Elsevier Science B.V.