Selective lesions by manganese and extensive damage by iron after injection into rat striatum or hippocampus.
Regional 45Ca2+ accumulation and analysis of monoamines and metabolites in dissected tissues were used to localize, quantify, and characterize brain damage after intracerebral injections of Mn2+ into striatum and hippocampus. The specificity of Mn(2+)-induced lesions is described in relation to brain damage produced by local Fe2+ or 6-hydroxydopamine (6-OHDA) injections. In striatum, Fe2+ and Mn2+ produced dose-dependent (0.05-0.8 mumol) dopamine (DA) depletion, with Fe2+ being 3.4 times more potent than Mn2+. Studies examining the time course of changes in monoamine levels in striatum following local application of 0.4 mumol of Mn2+ revealed maximal depletion of all substances investigated (except 5-hydroxyindoleacetic acid) after 3 days. The effects on DA (87% depletion at day 3) and its major metabolites were most pronounced and lasted until at least 90 days (40% depletion), whereas serotonin and noradrenaline levels recovered within 21 and 42 days, respectively. In addition, levels of 3-methoxytyramine, which is used as an index of DA release, also recovered within 42 days, indicating a functional restoration of DA neurotransmission despite substantial loss of DA content. Intrastriatal Mn2+ (0.4 mumol) produced time-dependent 45Ca2+ accumulation in striatum, globus pallidus, entopeduncular nucleus, several thalamic nuclei, and substantia nigra pars reticulata ipsilateral to the injection site. In contrast, 6-OHDA injected at a dose equipotent in depleting DA produced significantly less 45Ca2+ accumulation in striatum and globus pallidus and no labeling of other brain areas, whereas Fe2+ (0.4 mumol) produced extensive 45Ca2+ accumulation throughout basal ganglia, accumbens, and cerebral cortex. In hippocampus, high Mn2+ (0.4 mumol) produced limited 45Ca2+ accumulation in subiculum and dentate gyrus, whereas low Fe2+ (0.1 mumol) produced widespread 45Ca2+ accumulation throughout hippocampus, thalamus, and cerebral cortex. It is concluded that (a) Mn2+ is selectively neurotoxic to pathways intrinsic to the basal ganglia, (b) intrastriatal injections can be used as a model for systemic Mn2+ intoxications, and (c) high endogenous Fe3+ and/or catecholamine levels potentiate the neurotoxicity of Mn2+.
Sloot
W N
WN
Department of Neurotoxicology and Applied Neuroscience, TNO Medical Biological Laboratory, Rijswijk, The Netherlands.
van der Sluijs-Gelling
A J
AJ
Gramsbergen
J B
JB
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D001679:Biogenic Amines / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage / Q000633:toxicity*; D007700:Kinetics; D008297:Male; D008345:Manganese / Q000008:administration & dosage; D020149:Manganese Poisoning; D009498:Neurotoxins / Q000633:toxicity*; D009638:Norepinephrine / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
D001679:Biogenic Amines; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D008345:Manganese; D006897:Hydroxyindoleacetic Acid; D016627:Oxidopamine; D007501:Iron; D002118:Calcium; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid