VA-045, A NOVEL APOVINCAMIC ACID-DERIVATIVE ATTENUATES NEURONAL INJURY-INDUCED BY HYPOXIA OR BY EXCITATORY AMINO-ACIDS IN CULTURES OF RAT CORTICES

Effects of VA-045, a novel apovincaminic acid derivative, on neuronal damage induced by hypoxia or by excitatory amino acids (glutamate (Glu ), N-methyl-D-aspartate and kainate) were examined in cultures of the rat cortices. The extent of cell injury was quantified by measuring la ctic dehydrogenase activity released from the damaged cells into the c ulture medium. VA-045 at concentrations between 1 mu M and 30 mu M sig nificantly attenuated this neuronal damage and exceeded those of vinpo cetine. VA-045 had no significant binding affinity to Glu receptor sub types. The cytoprotection of VA-045 does not seem to be the result of antagonism at Glu receptors. VA-045 inhibited lipid peroxide productio n in brain homogenates. Vitamin E also had this antioxidant effect, bu t did not attenuate the hypoxia-induced neuronal damage. A cAMP analog ue and a phosphodiesterase (PDE) inhibitor also attenuated the hypoxia -induced neuronal damage. As VA-045 inhibits the activity of PDE, the effect of VA-045 may possibly relate to cAMP cascade. VA-045 may prove to be efficacious for the treatment of disorders related to cerebral neuronal injury.