Manganese neurotoxicity: a model for free radical mediated neurodegeneration?

Abstract

In man, manganese neurointoxication is characterised in the early phase by behavior reminiscent of that observed in schizophrenia. During chronic manganese intoxication the neuropsychiatric symptoms manifested earlier disappear and are followed by a permanent neurological phase typified by extrapyramidal symptoms similar to those of Parkinson's disease. Study of manganese intoxication in animals may provide important clues towards elucidation of the biochemical defect underlying neuropsychiatric as well as extrapyramidal disease. Investigations in our laboratory suggest that neurotoxicity of manganese is an exaggeration of function in normal neuronal homeostasis. Manganese neurointoxication in neonatal rats resulted in significant depression of lipid peroxidation in several rat brain regions examined. In the striatum, lipid peroxidative activity was abolished, an effect which may be related to alteration in neurotransmitters often observed in the striatum of manganese treated rats. The chronic, extrapyramidal stage of manganism, may ensue when excess Mn2+ is oxidised to higher valency forms where it can potentiate the autoxidation of catecholamines, like dopamine, resulting in concomitant formation of free radicals and cytotoxic quinones. This latter effect may arise preferentially in the substantia nigra, where neuromelanin is formed nonenzymatically by autoxidation of dopamine.

Direct effects of manganese compounds on dopamine and its metabolite Dopac: An in vitro study

“…Parallel studies using Mn 2+ -pyrophosphate or a 1000-fold molar excess of MnCl 2 (Mn 2+ ) or MnSO 4 (Mn 2+ ) resulted in no reaction with L-DOPA. However, the time scale of this study was less than 5 sec, whereas Mn 2+ -driven oxidation of catecholamines apparently occurs much slower (Donaldson et al, 1982), as was the case in our studies. In fact, when known amounts of DA were incubated with Mn (Fig.…”

“…Our results are consistent with previous studies showing that Mn can decrease DA levels. For example, Poirier et al, (1985) and Donaldson et al, (1982) demonstrated that Mn 2+ increases the rate of DA autooxidation in vitro, whereas others have reported that in vivo MnCl 2 treatment resulted in a decrease in striatal DA in rats (Autissier et al, 1982;Tran et al, 2002).…”

“…However, the basal ganglia are oxygen-rich and, potentially, Mn could be oxidized to a species with high valence states (Donaldson et al, 1982). One hypothesis put forth to explain Mn neurotoxicity is that Mn 2+ can undergo redox cycling reactions with Mn 3+ leading to dopaminergic toxicity, with Mn 3+ being the reactive species responsible for toxicity (Archibald and Tyree, 1987).…”

“…Nevertheless, studies show that dopamine (DA), the principal neurotransmitter that is severely reduced in the striatum of Parkinson's disease patients, is also reduced by Mn both in vivo (Parenti et al, 1986) and in vitro (Vescovi et al, 1991) exposure paradigms. This reduction of DA may be due, at least in part, to direct oxidation of this neurotransmitter by Mn (Donaldson et al, 1982).…”

Modulation of oxidative events by multivalent manganese complexes in brain tissue

“…In spite of extensive research efforts, the evidence for such speculations of manganese pro-oxidant activity, based primarily on use of the divalent salt manganese chloride (MnCl 2 ), has been conflicting. Manganese has been implicated in enhancing dopamine auto-oxidation and oxidative nigral [10,[13][14][15], and in inflicting damage similar to that of other mitochondrial toxins such as carbon monoxide and cyanide [16]. In evaluations of the oxidative character of manganese, several groups have attributed accelerated ROS formation to both the divalent and trivalent states of the metal [17,18].…”