Asiatic acid derivatives protect cultured cortical neurons from glutamate-induced excitotoxicity

Asiatic acid, a triterpene of Centella asiatica (L.) Urban (Umbelliferae), has been patented as a treatment for dementia and an enhancer of cognition by the Hoechst Aktiengesellschaft (EP 0 383 171 A2). We modified the chemic al structure of asiatic acid and obtained 36 derivatives of asiatic acid in an attempt to prepare neuroprotective compounds that were more efficacious than asiatic. acid itself. The neuroprotective activities of these derivat ives were evaluated using primary cultures of rat cortical neurons insulted with the neurotoxin, glutamate, as an in vitro screening system. Among the semi-synthesized derivatives, three derivatives significantly mitigated th e neurotoxicity induced by glutamate in this screening system. The neuropro tective activities of these 3 derivatives appeared to be more powerful than that of asiatic acid itself. These 3 derivatives significantly attenuated decreases in the levels of glutathione, glutathione peroxidase and other en zymes, which participate in the cellular defense mechanisms blunting oxidat ive stress. Furthermore, they significantly reduced the overproduction of N O induced by glutamate. These results showed that these derivatives of asia tic acid exerted significant neuroprotective effects on cultured cortical c ells by their potentiation of the cellular oxidative defense mechanism. The refore, these agents may prove to be efficacious in protecting neurons from the oxidative damage caused by exposure to excess glutamate.