Oxidative Basis of Manganese Neurotoxicity

Abstract

Exposure to excessive levels of manganese, an essential trace element, can evoke severe psychiatric and extrapyramidal motor dysfunction closely resembling Parkinson's disease. The clinical manifestations of manganese toxicity arise from focal injury to the basal ganglia. This region, characterized by intense consumption of oxygen and significant dopamine content, can incur mitochondrial dysfunction, depletion of levels of peroxidase and catalase, and catecholamine biochemical imbalances following manganese exposure. The site specificity of the pathology and the nature of the cellular damage caused by manganese have been attributed to its capacity to produce cytotoxic levels of free radicals. However, support for such a pro-oxidant role for manganese has been largely limited to inferences drawn from histopathological observations. More recently, research efforts into the molecular details of manganese toxicity have provided evidence of an etiological relationship between oxidative stress and manganese-related neurodegeneration. This review focuses on studies that evaluate the redox chemistry of manganese during the neurodegenerative process and its molecular consequences.

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

“…While DES exhibited substantial protective effects for MnCl 2 even at a concentration of 1μM, only 10μM DES had protective effects against 10μM MnPO 4 with little to no protective ability when incubated with 100μM MnPO 4 . Previous studies indicate that the pro-oxidant activity of MnCl 2 is exhausted in the presence of 500-fold lower concentrations of desferioxamine (HaMai and Bondy, 2004). Data from the present study appears to support the presence of trace amounts of Mn 3+ in MnCl 2 solutions and corrobate this finding.…”

“…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). The increased toxicity of Mn 3+ can be partially explained by the four unpaired d orbital electrons which results in a highly unstable atom with an elevated redox potential compared to the more thermodynamically stable Mn 2+ (HaMai and Bondy, 2004). Archibald and Tyree (1987) demonstrated that when L-DOPA was added to a physiological buffer containing Mn 3+ -pyrophosphate, a discernable color change was produced.…”

“…EDTA and EGTA are chelators of divalent metals such as Mn 2+ and when coadministered with MnPO 4 , both chelators had considerable protective effects on DA. Desferioxamine (DES), a highly selective chelator of trivalent metals (HaMai and Bondy, 2004), provided protection at 1 and 10 μM against media Dopac/DA degradation by MnCl 2 that was present in 100-or 1000-fold molar excess. Thus, this provided evidence that trace amounts of Mn 3+ were present in the MnCl 2 -containin exposure medium.…”

“…Furthermore, the presence of two hydroxyl groups at adjacent 3-and 4-positions on DA and Dopac will allow Mn 2+ and Mn 3+ to redox cycle and generate semiquinones and orthoquinone by the sequential oxidation of catecholamines via several one electron transfer reactions (Donaldson, 1987). According to a more recent mechanism proposed by HaMai and Bondy (2004), the pro-oxidant activity of Mn 2+ is dependent on trace amounts of Mn 3+ , which may facilitate a small portion of Mn 2+ to oxidize to Mn 3+ . This synergistic relationship between Mn 2+ and Mn 3+ results in continuous redox cycling (HaMai and Bondy, 2004).…”

“…However, the possibility exists that in the presence of DA and Dopac some Mn becomes trivalent and initiates redox cycling (HaMai and Bondy, 2004). Our next goal was to determine whether or not Mn 3+ was playing a role in the Mn-mediated depletion of DA and Dopac.…”