Mechanisms of m-dinitrobenzene-induced selective neurotoxicity and the roles of brain glutathione

m-Dinitrobenzene (m-DNB) is a neurotoxin producing selective damage in the brain stem. The mechanisms of the selective neurotoxicity induced by this compound have been investigated in this project. In vitro studies demonstrated that brain has considerable nitroreductive capacity towards m-DNB. m-Nitroaniline was the main metabolite produced, attaining up to 66% of the original concentration of m-DNB while nitrosonitrobenzene was also detectable in brain slices. Glutathione (GSH) and ascorbic acid were able to clinically reduce nitrosonitrobenzene. The results indicate that in situ reduction of m-DNB may play an important role in the m-DNB-induced neurotoxicity.;Both GSH and ascorbic acid were lower in normal brain stem. Striatum had the highest level of GSH while hippocampus had the highest level of ascorbic acid. In contrast, free malondialdehyde (MDA) was higher in the brain stem than the other areas. Brain stem areas were more sensitive to the BSO-induced GSH depletion since GSH half life in those areas were shorter than in other brain areas. These results indicate a lower antioxidant capacity and a higher spontaneous oxidative stress in brain stem. This may partially explain the susceptibility of brain stem to neurotoxic xenobiotics.;In order to test the hypothesis that GSH status in brain plays an important role in the selective neurotoxicity of m-DNB, the susceptibility of the rat to intoxication was studied in 6 month old animals that show naturally lower GSH levels in brain and also in young adult animals treated with BSO to deplete brain GSH. Control adult animals developed brain stem lesions after 4 doses of m-DNB(4x10mg/kg); but 6 month old animals showed these changes after 3 doses, while BSO-treated animals had brain stem lesions after only 1 dose of DNB. This demonstrated that brain GSH status is likely to be an important factor in determining regional sensitivity to gliovascular damage induced by m-DNB.;A close parallel between developmental changes of hippocampal GSH and cysteine suggests that cysteine may be a rate limiting factor for brain GSH synthesis during the early period of life.