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

Res Commun Mol Pathol Pharmacol. Jul-Aug 2000;108(1-2):75-86.

Abstract

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 chemical 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 derivatives 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 the neurotoxicity induced by glutamate in this screening system. The neuroprotective 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 enzymes, which participate in the cellular defense mechanisms blunting oxidative stress. Furthermore, they significantly reduced the overproduction of NO induced by glutamate. These results showed that these derivatives of asiatic acid exerted significant neuroprotective effects on cultured cortical cells by their potentiation of the cellular oxidative defense mechanism. Therefore, these agents may prove to be efficacious in protecting neurons from the oxidative damage caused by exposure to excess glutamate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Calcium / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acids / toxicity*
  • Glutamic Acid / toxicity*
  • Glutathione / metabolism
  • Glutathione Peroxidase / metabolism
  • Malondialdehyde / metabolism
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neuroprotective Agents / pharmacology*
  • Nitrates / metabolism
  • Oxidative Stress / drug effects
  • Pentacyclic Triterpenes
  • Rats
  • Rats, Sprague-Dawley
  • Triterpenes / pharmacology*

Substances

  • Antioxidants
  • Excitatory Amino Acid Antagonists
  • Excitatory Amino Acids
  • Neuroprotective Agents
  • Nitrates
  • Pentacyclic Triterpenes
  • Triterpenes
  • Glutamic Acid
  • Malondialdehyde
  • asiatic acid
  • Glutathione Peroxidase
  • Glutathione
  • Calcium