Neurotoxicity, metal-induced

Knowledge of the intracellular thermodynamics and kinetics of metal metabolism may become useful in the design of compounds that alter intracellular metal ion availability. This in turn may be useful in controlling such biological phenomena as cancer cell proliferation, disorders of metal metabolism, and metal-induced neurotoxicity. 

It is well known that a large number of chemical substances, including toxic metals and metalloids such as arsenic, cadmium, lead, and mercury, cause cell injury in the kidney. With metal-induced neurotoxicity, factors such as metal-binding proteins, inclusion bodies, and cell-specific receptor-like proteins seem to influence renal injury in animals and humans. It is of interest to note that certain renal cell populations become the targets for metal toxicity, while others do not. In fact, the target cell populations handle the organic and common inorganic nephrotoxicants differently. ... 

Reactive oxygen species production is largely catalyzed by transition metals (especially copper and iron), and oxidative stress plays a critical role in AD pathogenesis. In one study, the association of metal levels and Ap toxicity was demonstrated by (i) the effect on cell viability by metal alone and in the combination with APP and Ap, (ii) Ap-induced neurotoxicity relevant to oxidative stress indicated by ROS production, and (iii) APPsw cells expressed APP and generated Ap, so that Ap Cu2+ and APP Cu2+ can catalyze more ROS generation than APP cells that only expressed APP. 

Nicotine shows protective effects against Ap-induced neurotoxicity in vivo and in vitro. Although nicotine acts on nAChRs, it also contains metal chelating abilities. It has been shown that maternal nicotine exposure resulted in a reduction of the copper content in the neonatal lung. In addition, evidence has been accumulated that nicotine might chelate metals. Indeed, nicotine reduces the levels of copper and zinc in senile plaques and neuropil, counteracting the undesirable metal accumulation. 

Zhang J, Liu Q, Chen Q, Liu NQ, Li FL, Lu ZB, Qin C, Zhu H, Huang YY, He W, Zhao BL. 2006. Nicotine attenuates beta-amyloid-induced neurotoxicity by regulating metal homeostasis. FASEB J 20 1212-1214. 

Uptake of Toxic Divalent Metal Ions in Neurotoxicity Induced by Kainate... 

The neurotoxic properties of Af) have also been shown to be associated with methionine at residue 35 of A (Met35) (Butterfield and Boyd-Kimball, 2005). The substitution of methionine by norleucine from Af) abolishes free radical production, protein oxidation, and toxicity to hippocampal neurons (Butterfield and Boyd-Kimball, 2005). In addition, substitution of a carbon atom for the S atom of methionine completely abrogates A (l-42) neurotoxicity (Yatin et al., 1999 Butterfield and Kanski, 2002), and in vivo studies indicate methionine residue 35 is central for A -induced oxidative damage (Yatin et al., 1999). Studies from our laboratory (Varadarajan et al., 2000) and others (Curtain et al., 2001) showed that Cu bound to Af)(l-42) interacts with Met35 residue to produce free radicals in the absence of methionine in A ( 1 -42) redox metal ions play no role in the oxidative stress and neurotoxicity induced by the peptide (Varadarajan et al., 2000, 2001). Taken together these results are consonant with the notion that Af)-induced protein oxidation may in part account for neurodegeneration in AD brain (Butterfield and Boyd-Kimball,... 

Protein oxidation is certainly one of the most predominant protein modifications in neurodegeneration. On the other hand, a possible way by which a protein aggregate could lead to neurotoxicity would be via mediation of radical formation due to metabolic impairment of affected cells. This process again leads to secondary protein oxidation and aggregate modification. One of the best-studied proteins is the amyloid peptide, which seems capable of inducing free radical production in Alzheimer s disease [134]. Amyloid peptide is able to bind metals and these are able to produce radicals through the Fenton reaction [135,136]. 

Importantly, the neuropathological and clinical characteristic features of MPTP-induced parkinsonism invariably resemble idiopathic Parkinson s disease rather more intimately than anyother previous human or experimented animal disorder exhibited by toxins, viruses, metals, or other modes. In short, the molecular pathophysiology of the ensuring MPTP neurotoxicity has virtually decephered the mystery surrounding the neurodegenerative mechanisms particularly associated with the idiopathic parkinsonism. 

Yang et al (2005) have proposed an alternate pathway of manganese induced neurotoxicity that involved eukaryotic ACDP (ancient conserved domain protein) family protein in metal homoeostasis. These authors employed the baker s yeast Saccharomyces cerevisiae as a model system to identify genes that contributed to manganese-related damage. 

Allowing that the above transfer system involving Mn does occur, the cause of manganese neurotoxicity is still little understood. Archibald and Tyree [75] propose that the ability of to attack catecholamines indicates that this metal ion is toxic in itself, while other workers [76-78] see the toxicity as being due to a variety of causes such as autooxidation of dopamine, decreased glutathione (GSH) levels [64,79], reduced GSH peroxidase and brain catalase [79], and Mn -induced production either of toxic catecholamines and quinones [77] or of reactive oxo species such as superoxide, hydroxide radicals, or hydrogen peroxide [77,80,81]. A further excellent summary of much of the above detail is given by Donaldson and Barbeau [82]. 

The uranyl ion (UO ) is the most stable species, easily forms complexes, which are both well dissolved in water and represent the form present in the mammalian body [154]. It may react with biological molecules to produce cellular necrosis (cell death) and/or atrophy in the tubular walls in the kidneys, resulting in a diminished ability to filter impurities from the blood. There is no data available for long-term effects of uranium-induced developmental toxicity on humans. The information from intermediate-term studies on animals using the uranyl ion, oxides and rarely the metal [155, 156] demonstrate that DU is mutagenic and has neurotoxic properties [157]. 

It is also known that the toxic effects of heavy metals may be reduced in many organisms by binding to specific ligands. Metallothionein plays a crucial role among these specific ligands. In relation to trace elements, MT might serve as an indicator of an environmental pollution and exposure to this pollution. Increased level of MT-I and -II in tissue(s) indicates an exposure to trace elements, respectively heavy metals. MT-III is non-inducible and probably plays an important role in the metabolism of zinc and elements that are involved in neurotoxicity [128]. 

---