Brain macrophages (BM), a subpopulation of microglia, have the ability to kill neurons by producing reactive oxygen intermediates. Cocultures of neurons and macrophages derived from the cerebral cortex of rat embryos were used to look for regulation of BM neurotoxicity. Isoproterenol (10(-7) M), a beta-adrenergic agonist, induced a significant inhibition of BM neurotoxicity and this effect was abolished in the presence of propranolol, a beta-adrenergic antagonist. BM neurotoxicity was also reduced in the presence of prostaglandin E2 (10(-8), 10(-6) M), a metabolite derived from arachidonic acid. These results suggest endogenous mechanisms of neuroprotection operating either during development or following lesions.