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) in rat striatum after Mn2+ intoxication. For this purpose, DA depletions were assessed concomitant with in vivo 2,3- and 2,5-dihydroxybenzoic acid (DHBA) formation from the reaction of salicylate with OH, of which 2,3-DHBA is a nonenzymatic adduct. Following intrastriatal Mn2+ injection, marked 2,3-DHBA increases were observed in a time- and dose-dependent fashion reaching maximum levels at 6-18 h and a plateau beyond 0.4 micromol (fourfold increase). The delayed increase of 2,3-DHBA levels suggestS that Mn2+ induces OH formation in the living brain by an indirect process. The early DA depletion (2 h) and relatively late OH formation (6 h) indicate independent processes by Mn2+. In addition, depletion of DA (about 90%) by reserpine pretreatment not significantly alter Mn2+-induced 2,3-DHBA formation or the extent of DA depletion, suggesting that DA or DA autoxidation are not participating in Mn2+-induced OH formation in vivo. Furthermore, Mn2+ injection did not significantly alter the low molecular weight weight iron pool in striatum, and co-injections of the iron-chelator deferoxamine with Mn(2+) into striatum did not significantly attenuate Mn(2+)-induced 2,3-DHBA formation. These findings suggest no role of chelatable iron in generation of Mn(2+)-induced OH, but do not exclude a role for mitochondrial heme-iron or peroxynitrite (Fe-indepeNdent) in Mn2+-induced OH formation.
Sloot
W N
WN
TNO Nutrition and Ffood Research Institute, Department of Bio-pharmaceutical Analysis, Zeist, The Netherlands.
Korf
J
J
Koster
J F
JF
De Wit
L E
LE
Gramsbergen
J B
JB
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D004298:Dopamine / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D017665:Hydroxyl Radical / Q000378:metabolism*; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D008970:Molecular Weight; D009498:Neurotoxins / Q000494:pharmacology; D009994:Osmolar Concentration; D016627:Oxidopamine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D013997:Time Factors
D007502:Iron Chelating Agents; D009498:Neurotoxins; D017665:Hydroxyl Radical; D008345:Manganese; D012110:Reserpine; D016627:Oxidopamine; D007501:Iron; D003676:Deferoxamine; D004298:Dopamine