THE ATTENUATION OF KAINATE-INDUCED NEUROTOXICITY BY CHLORMETHIAZOLE AND ITS ENHANCEMENT BY DIZOCILPINE, MUSCIMOL, AND ADENOSINE RECEPTOR AGONISTS

Systemically administered kainate (10 mg . kg(-1)) caused neuronal los s in both the hippocampus and the entorhinal regions of the rat brain. This resulted in a loss of 68.3 +/- 13.8 and 53.3 +/- 12.8% of pyrami dal neurones in the hippocampal CA1 and CA3a regions, respectively. Ch lormethiazole attenuated the loss of neurones in the hippocampal cell layers CA1 (cell loss 10 +/- 3.2%) and CA3a (cell loss 10 +/- 7.7%). T he neuroprotective activity of chlormethiazole was apparent in the pre sence or absence of a low dose of clonazepam (200 mu g . kg(-1) ip). T he kainate-induced damage could also be measured by the increase in bi nding of the peripheral benzodiazepine ligand ([H-3]PK11195) in the hi ppocampus. In kainate-treated rats there was a 350-500% increase in bi nding indicative of reactive gliosis. Chlormethiazole prevented this e levation in a dose-and time-dependent manner, with an ED50 of 10.64 mg . kg(-1) and an effective therapeutic window from 1 to 4 h posttreatm ent. Dizocilpine also attenuated damage significantly. The GABA(A) ago nist muscimol was also able to attenuate the increase in [3H]PK11195 b inding in a dose-dependent manner, with an ED50 Of approximately 0.1 m g . kg(-1). If muscimol, dizocilpine, or the adenosine A(1) receptor a gonist R-N-6-phenylisopropyl-adenosille were administered together wit h chlormethiazole at their respective ED25 doses, a potentiation was a pparent in the degree of neuroprotection. It is concluded that the com bination of neuroprotective agents with different mechanisms of action can lead to a synergistic protection against excitotoxicity. (C) 1997 Academic Press.