Manganese injection into the rat striatum produces excitotoxic lesions by impairing energy metabolism.
There is compelling evidence that excessive exposure to manganese (Mn) produces neurotoxicity, especially in the basal ganglia, resulting in a dystonic Parkinsonian disorder. Several experimental or clinical observations suggest that Mn neurotoxicity could involve impairment of energy metabolism. We examined the neurotoxic effects of Mn following local intrastriatal injection. Three hours after the injection of 2 mumol of MnCl2 into rat striatum, ATP levels were reduced to 51% of the control side and lactate level were increased by 97%, indicating an impairment of oxidative metabolism. Neurochemical analysis of the striata 1 week after Mn injection showed changes consistent with a N-methyl-D-aspartate (NMDA) excitotoxic lesion. Dopamine, gamma-aminobutyric acid, and substance P concentrations showed dose-dependent significant decreases, but concentrations of somatostatin-like immunoreactivity and neuropeptide Y-like immunoreactivity were unchanged. The lesions were blocked by prior removal of the cortico-striatal glutamatergic input or by treatment with the noncompetitive NMDA antagonist MK-801. These findings indicate that Mn neurotoxicity involves a NMDA receptor-mediated process similar to that we have previously found with two characterized mitochondrial toxins, aminooxyacetic acid, and 1-methyl-4-phenylpyridinium. Our results show that Mn may produce neuronal degeneration by an indirect excitotoxic process secondary to its ability to impair oxidative energy metabolism.
Brouillet
E P
EP
Neurochemistry Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Shinobu
L
L
McGarvey
U
U
Hochberg
F
F
Beal
M F
MF
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003655:Decerebrate State; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects*; D007267:Injections; D008297:Male; D008345:Manganese / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D008345:Manganese; D016291:Dizocilpine Maleate