Neuroprotective effect of 5-HT1A receptor agonist, Bay X 3702, demonstrated in vitro and in vivo.

摘要

It has been shown recently that Bay X 3702 ((-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1, 2,-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride), a highly potent and selective 5-HT1A receptor agonist, has a neuroprotective potency associated with its ability to inhibit ischemia-induced excessive release of glutamate. 5-HT1A receptors are highly expressed in brain areas, such as the hippocampus and the cerebral cortex, sensitive to neuronal damage induced by ischemic stroke or brain trauma. Therefore, we investigated 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 neuronal necrosis as evaluated 18 h later by trypan blue staining and morphological criteria. However, treatment with Bay X 3702 (0.001 to 1 microM) reduced the number of damaged neurons, and preserved cell morphology and integrity of the neuronal network. Bay X 3702 was added immediately after the end of exposure to glutamate and was present until the evaluation of neuronal damage. Furthermore, the neuroprotective activity of Bay X 3702 (0.1 microM) was abolished by WAY 100635 (N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl cyclo-hexanecarboxamide) (1 microM), a selective 5-HT1A receptor antagonist, indicating that the neurorescuing activity of Bay X 3702 was mediated via stimulation of 5-HT1A receptors. Additionally, we attempted to find whether the drug could protect rat brain tissue from ischemic insult due to permanent occlusion of the middle cerebral artery in rats. Bay X 3702 (12 and 40 microg/kg), infused within a period of 4 h, immediately after induction of ischemia greatly reduced cortical infarct volume (57 and 55% of controls, respectively) suggesting that this drug might be useful for the treatment of acute cerebral infarction.