NEUROPROTECTIVE EFFECT OF 5-HT1A RECEPTOR AGONIST, BAY-X-3702, DEMONSTRATED IN-VITRO AND IN-VIVO

it has been shown recently that Bay x 3702 )methyl]amino]butyl]-1,2,-b enzisothiazol-3(2H)-one I,l-dioxide monohydrochloride), a highly poten t and selective 5-HT1A receptor agonist, has a neuroprotective potency associated with its ability to inhibit ischemia-induced excessive rel ease of glutamate. 5-HT1A receptors are highly expressed in brain area s, such as the hippocampus and the cerebral cortex, sensitive to neuro nal damage induced by ischemic stroke or brain trauma. Therefore, we i nvestigated whether Bay x 3702 can rescue cultured hippocampal neurons subjected to excitotoxic damage. The hippocampal neurons exposed to 0 .5 mM L-glutamate for 1 h had pronounced damage characteristic of neur onal necrosis as evaluated 18 h later by trypan blue staining and morp hological criteria. However, treatment with Bay x 3702 (0.001 to 1 mu M) reduced the number of damaged neurons, and preserved cell morpholog y and integrity of the neuronal network. Bay x 3702 was added immediat ely after the end of exposure to glutamate and was present until the e valuation of neuronal damage. Furthermore, the neuroprotective activit y of Bay x 3702 (0.1 mu M) was abolished by WAY 100635 (methoxyphenyl) -1-piperazinyl]ethyl]-N-2-pyridinyl cyclo-hexanecarboxamide) (1 mu M), a selective 5-HT1A receptor antagonist, indicating that the neuroresc uing activity of Bay x 3702 was mediated via stimulation of 5-HT1A rec eptors. Additionally, we attempted to find whether the drug could prot ect rat brain tissue from ischemic insult due to permanent occlusion o f the middle cerebral artery in rats. Bay x 3702 (12 and 40 mu g/kg), infused within a period of 4 h, immediately after induction of ischemi a greatly reduced cortical infarct volume (57 and 55% of controls, res pectively) suggesting that this drug might be useful for the treatment of acute cerebral infarction. (C) 1998 Elsevier Science B.V. All righ ts reserved.