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Selective lesions by manganese and extensive damage by iron after injection into rat striatum or hippocampus
W N Sloot1, A J van der Sluijs-Gelling, J B Gramsbergen
1Department of Neurotoxicology and Applied Neuroscience, TNO Medical Biological Laboratory, Rijswijk, The Netherlands.
Abstract:
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+.
Insights
Manganese (Mn2+) selectively damages basal ganglia pathways, unlike iron (Fe2+) or 6-hydroxydopamine (6-OHDA). Intrastriatal Mn2+ injections offer a model for systemic manganese intoxication, showing long-term dopamine depletion.
Area of Science:
- Neuroscience
- Neurotoxicology
- Biochemistry
Background:
- Investigating the neurotoxic effects of manganese (Mn2+) is crucial for understanding its impact on brain function.
- Comparing Mn2+ neurotoxicity with other agents like iron (Fe2+) and 6-hydroxydopamine (6-OHDA) helps elucidate specific mechanisms.
- The basal ganglia and hippocampus are key brain regions affected by metal ion exposure.
Purpose of the Study:
- To localize, quantify, and characterize brain damage induced by intracerebral Mn2+ injections.
- To compare the neurotoxic specificity of Mn2+ with Fe2+ and 6-OHDA in the striatum and hippocampus.
- To establish intrastriatal Mn2+ injections as a model for systemic manganese intoxication.
Main Methods:
- Regional 45Ca2+ accumulation was measured to assess brain damage.
- Analysis of monoamines and their metabolites quantified neurochemical changes.
- Intracerebral injections of Mn2+, Fe2+, and 6-OHDA were administered into the striatum and hippocampus.
Main Results:
- Mn2+ selectively induced dopamine depletion in the striatum, with effects lasting up to 90 days.
- Fe2+ was more potent than Mn2+ in causing dopamine depletion but produced broader 45Ca2+ accumulation.
- 6-OHDA showed less 45Ca2+ accumulation compared to Mn2+ and Fe2+.
- Mn2+ primarily affected basal ganglia pathways, while Fe2+ caused widespread accumulation in multiple brain areas.
Conclusions:
- Mn2+ is selectively neurotoxic to pathways within the basal ganglia.
- Intrastriatal Mn2+ injections serve as a valid model for studying systemic manganese intoxication.
- Endogenous iron (Fe3+) and catecholamine levels may potentiate Mn2+ neurotoxicity.