Neurotoxicity effects, mitochondrial

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

In vitro systems have been developed to try and understand the mechanism of action of maneb. In particular, the mechanism of toxicity of maneb on the central nervous system using synaptosomal and mitochondrial preparations from brain tissue has been utilized. These studies have shown that maneb has adverse effects on the dopaminergic system, via mechanisms that relate to mitochondrial inhibition and altered neurotransmitter uptake. The genotoxic, cytotoxic, and neurotoxic effects of maneb have been studied using a variety of primary cultures as well as cell lines, including human lymphocytes. As noted above, maneb has little mutagenic potential. 

The neurotoxic effect of Pb has been associated with interference with the mitochondrial Na+/Ca anti-porter [59] and with the initiation of mitochon-dria-dependent apoptosis in rod photoreceptors [60]. Apparently, cytosohc Pb competes with Ca-+, leading to mitochondrial dysfunction. 

Interactions between Ap and x-protein are also related to mitochondrial dysfunction [20]. Ap and x-protein can mutually reinforce their neurotoxic effects by inhibiting the function of mitochondria and their axonal transport. Ap-induced stress affects endoplasmic reticulum (ER) [21]. Experimental findings support the hypothesis that just oligomers are the toxic forms of the x-protein showing during the AD [22]. 

Metamfetamine-induced neurotoxicity in animals, especially involving effects on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascade, has been comprehensively reviewed (40). Metamfetamine increases the activity of dopamine, mainly by inhibiting the dopamine transporter. However, this does not explain why psychosis persists even when the metamfetamine is no longer present in the body (41). Chronic metamfetamine use has been reported to reduce dopamine transporter density in the caudate/putamen and nucleus accumbens. However, previous studies have been criticized for not controlling for other drug use. 

Intoxication may present as inebriation and drowsiness similar to ethanol use. Other symptoms are vomiting, diarrhea, delirium and agitation, back and abdominal pain, and clammy skin. Toxic effects usually follow a latent period of several hours. Formate inhibits mitochondrial cytochromes resulting in neurotoxicity. Ocular signs include blurred vision, dilated pupils, and direct retinal toxicity with optic disc hyperemia and ultimately permanent blindness [91]. Cerebral hemorrhagic necrosis has been reported [92]. Severe poisoning may result in Kussmaul respiration, inspiratory apnea, coma, and death. Urine samples may have the characteristic smell of formaldehyde. An elevated serum osmolal gap from methanol will be evident early in presentation but may disappear after approximately 12 hours. At this time, an elevated anion gap metabolic acidosis from retained formate may be evident. 

Bajijiasu. Chen et al. [248] studied the protective effect ofBajijiasu (P-D-fructofuranosyl (2-2) p-D-fructofuranosyl), a dimeric fructose isolated from the Chinese herb radix Morinda officinalis, on Ap-induced neurotoxicity in pheochromocytoma (PC12) cells. Bajijiasu reversed the reduction in cell viability induced by exposure to Ap25 35, reduced Ap25 35-induced toxicity, decreased the accumulation of intracellular ROS and the lipid peroxidation product malondialdehyde, upregulated expression of glutathione reductase and superoxide dismutase, prevented depolarization of the mitochondrial membrane potential ( Em), and blocked... 

Thymoquinone. Thymoquinone (TQ) is the main constituent of the oil extracted from Nigella sativa seeds, with antioxidant and anti-inflammatory effects. Treatment with TQ efficiently attenuates APi 2-induced neurotoxicity, inhibits the mitochondrial membrane potential depolarization and ROS generation caused by Api 2, restores synaptic vesicle recycling inhibition, partially reverses the loss of spontaneous firing activity, and inhibits A(f aggregation in vitro [291],... 

Effects attributed to chlordane exposure include blood dyscrasia, hepatotoxicity, neurotoxicity, immunotoxicity and cancer. Possible mechanisms of toxicity relevant to all target organs include the ability of chlordane and its metabolites to bind irreversibly to cellular macromolecules, inducing cell death or disrupting normal cell function. In addition, chlordane may increase tissue production of superoxide, which can accelerate lipid peroxidation, disrupting the function of cellular and subcellular membranes. Chlordane induces its own metabolism to toxic intermediates, which may exacerbate its hepatotoxicity. This may involve suppression of hepatic mitochondrial energy metabolism. 

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