In the present study, the protective effect of melatonin on sodium arsenite (arsenite)-induced apoptosis was investigated. Local infusion of arsenite elevated lipid peroxidation and depleted glutathione content in the infused substantia nigra (SN), as well as reduced striatal dopamine content. Systemic administration of melatonin diminished arsenite-induced oxidative injury. Furthermore, melatonin attenuated arsenite-induced increases in heat shock protein 70 and heme oxygenase-1 as well as phosphorylation of p38 mitogen-activated protein kinase and elevations in cyclooxygenase II and inducible nitric oxide synthase expression. Inhibition by melatonin of arsenite-induced apoptosis was determined by its attenuation of DNA fragmentation and terminal deoxytransferase-mediated dUTP-nick end labeling's positive cells in the infused SN of melatonin-treated rats. Melatonin reduced arsenite-induced apoptosis through mitochondrial and endoplasmic reticulum (ER) pathways. In the mitochondrial pathway, systemic melatonin inhibited arsenite-induced elevations in Bcl-2 and cytosolic cytochrome c as well as arsenite-induced reductions in procaspase-3 levels and elevations in active caspase-3 levels in the infused SN. Regarding the ER pathway, melatonin attenuated arsenite-induced elevations in activating transcription factor-4, CCAAT/enhancer binding protein (C/EBP) homologues protein, X-bon binding protein (XBP-1) and cytosolic immunoglobulin binding protein (BIP) as well as reductions in procaspase 12 levels. Moreover, aggregation of alpha-synuclein was reduced in the arsenite-infused SN of melatonin-treated rats. Our in vitro data showed that melatonin ameliorated arsenite-induced lipid peroxidation. Taken together, our data suggest that melatonin is neuroprotective against arsenite-induced oxidative injury in the nigrostriatal dopaminergic system of rat brain. Furthermore, the neuroprotective effects by melatonin on arsenite-induced apoptosis were mediated via inhibiting both mitochondrial and ER pathways. Accordingly, melatonin may be therapeutically useful for the treatment of arsenite-induced apoptosis in central nervous system.

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Antioxidative mechanisms of vitamin D3 were evaluated both in vitro and in vivo. A 4-h incubation of brain homogenates at 37 degrees C increased the formation of Schiff base fluorescent products of malonaldehyde, an indicator of lipid peroxidation. Incubation with vitamin D3 dose-dependently suppressed auto-oxidation. The antioxidative potency for inhibiting zinc-induced lipid peroxidation was as follows: vitamin D3 > Trolox (a water-soluble analogue of vitamin E) > or = beta-estradiol > melatonin. In the presence of high dose of desferrioxamine, a metal chelator, vitamin D3 attenuated auto-oxidation. These in vitro data indicate that vitamin D3 may act as a terminator of the lipid peroxidation chain reaction. The antioxidative effect of vitamin D3 on zinc-induced oxidative injury was verified using local infusion of vitamin D3 in vivo. Intranigral infusion of zinc elevated lipid peroxidation in the infused substantia nigra and depleted striatal dopamine content at 7 days after infusion. Furthermore, elevated cytosolic cytochrome c and DNA ladder, indicatives of apoptosis, were demonstrated in the infused substantia nigra. Simultaneous infusion of vitamin D3 and zinc prevented oxidative injury and apoptosis induced by zinc alone. The involvement of glia-derived neurotrophic factor (GDNF) expression was excluded since vitamin D3 did not alter GDNF level in the infused substantia nigra at 24 h or 4 days after intranigral infusion of vitamin D3. Our results suggest that vitamin D3, independent of upregulation of GDNF expression, may acutely prevent zinc-induced oxidative injuries via antioxidative mechanisms.

The study indicated that 98-kDa mite paramyosin is an important allergen.