Lead neurotoxicity: heme oxygenase and nitric oxide synthase activities in developing rat brain

Chronic lead (Pb) exposure has been shown to result in cognitive deficits in children. Diffusible nitric oxide (NO) is a biological messenger known to regulate long-term potentiation (LTP) in the developing nervous system. Carbon monoxide (CO), as in the case of NO was shown to be a messenger molecule in the brain. Our previous studies indicated significant changes in neuronal nitric oxide synthase (nNOS) in the developing brain following Pb-exposure [Chetty et al. (2001) Int. J. Toxicol. 20, 113-120]. In the present study, we investigated the effects of perinatal Pb-exposure on the activity of heme oxygenase (HO), the enzyme that produces CO by the catabolism of heme. Male Sprague-Dawley rats were exposed to 0.2% Pb-acetate gestationally and lactationally up to postnatal day (PND) 21. The specific activity of HO was determined in the hippocampus and the cerebellum of rat brain at PND 7, 14, 21 and 35. HO activity was higher in the hippocampus as compared to the cerebellum at any postnatal age. HO activity increased progressively up to PND 21 followed by a marginal decrease at PND 35. Perinatal Pb-exposure did not induce any significant change in HO activity as compared to control rats. However, in vitro treatment of microsomal supernatant fractions prepared from the cerebellum and the hippocampus to different (5-50 micro M) concentrations of Pb increased HO activity whereas the activity decreased at 100 micro M. The selective NOS inhibitors, nitroarginine (NA) and nitroindazole (NI) had no significant effect on HO activity; however, nNOS activity was inhibited in a concentration-dependent manner. In contrast, the selective HO-inhibitor, zinc protoporphyrin-IX (ZnPP) inhibited both HO and nNOS activity levels. The NO-donor, sodium nitroprusside (SNP) did not alter HO activity except at a higher (100 micro M) concentration. These data suggest that Pb-exposure selectively modulates nNOS but not HO in developing rat brain.