Events which lead to an increase in intracellular free radicals induce necrotic cell death of cultured cortical neurons. In the present study, we report that treatment with 1 microM (+/-)-SKF-38393 hydrochloride, a selective D1 agonist, as well as 100 microM trolox, a lipophilic vitamin E analogue, significantly prevented oxidative-related necrotic cell death following exposure to 10 microM Fe2+ or 1 mM buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase. The neuroprotective effect of (+/-)-SKF-38393 hydrochloride was partially reversed by addition of (+/-)-SKF-83566 hydrochloride, a selective D1 antagonist. Quinelorane dihydrochloride, a selective D2 agonist, did not influence free radical neurotoxicity. Interestingly, inclusion of (+/-)-SKF-38393 hydrochloride or quinelorane dihydrochloride did not attenuate apoptotic 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 for the treatment of various neurodegenerative diseases linked to oxidative stress.