MANGANESE-INDUCED HYDROXYL RADICAL FORMATION IN RAT STRIATUM IS NOT ATTENUATED BY DOPAMINE DEPLETION OR IRON CHELATION IN-VIVO

The present studies were aimed at investigating the possible roles of dopamine (DA) and iron in production of hydroxyl radicals ((OH)-O-.) i n rat striatum after Mn2+ intoxication. For this purpose, DA depletion s were assessed concomitant with in vivo 2,3- and 2,5-dihydroxybenzoic acid (DHBA) formation from the reaction of salicylate with (OH)-O-., of which 2,3-DHBA is a nonenzymatic adduct. Following intrastriatal Mn 2+ injection, marked 2,3-DHBA increases were observed in a time- and d ose-dependent fashion reaching maximum levels at 6-18 h and a plateau beyond 0.4 mu mol (fourfold increase). The delayed increase of 2,3-DHB A levels suggests that Mn2+ induces (OH)-O-. formation in the living b rain by an indirect process. The early DA depletion (2 h) and relative ly late (OH)-O-. formation (6 h) indicate independent processes by Mn2 +. In addition, depletion of DA (about 90%) by reserpine pretreatment did not significantly alter Mn2+-induced 2,3-DHBA formation or the ext ent of DA depletion, suggesting that DA or DA autoxidation are not par ticipating in Mn2+ induced (OH)-O-. formation in vivo. Furthermore, Mn 2+ injection did not significantly alter the low molecular weight iron pool in striatum, and co-injections of the iron-chelator deferoxamine with Mn2+ into striatum did not significantly attenuate Mn2+-induced 2,3-DHBA formation. These findings suggest no role of chelatable iron in generation of Mn2+-induced (OH)-O-., but do not exclude a role for mitochondrial heme-iron or peroxynitrite (Fe-independent) in Mn2+-indu ced (OH)-O-. formation. (C) 1996 Academic Press, Inc.