ATTENUATION OF OXIDATIVE NEURONAL NECROSIS BY A DOPAMINE D1 AGONIST IN MOUSE CORTICAL CELL-CULTURES

Events which lead to an increase in intracellular free radicals induce necrotic cell death of cultured cortical neurons. In the present stud y, we report that treatment with 1 mu M (+/-)-SKF-38393 hydrochloride, a selective D1 agonist, as well as 100 mu M trolox, a lipophilic vita min E analogue, significantly prevented oxidative-related necrotic cel l death following exposure to 10 mu M Fe2+ or 1 mM buthionine sulfoxim ine, an inhibitor of gamma-glutamylcysteine synthetase. The neuroprote ctive effect of (+/-)-SKF-38393 hydrochloride was partially reversed b y addition of (+/-)-SKF-83566 hydrochloride, a selective D1 antagonist . Quinelorane dihydrochloride, a selective D2 agonist, did not influen ce free radical neurotoxicity. Interestingly, inclusion of (+/-)-SKF-3 8393 hydrochloride or quinelorane dihydrochloride did not attenuate ap optotic cell death of cortical neurons deprived of serum. The present study provides evidence that (+/-)-SKF-38393 hydrochloride attenuates oxidative neuronal necrosis, which has unique therapeutic potential fo r the treatment of various neurodegenerative diseases linked to oxidat ive stress. (C) 1997 Academic Press.