No abstract

No abstract

In evaluating mechanisms of trimethyltin (TMT)-initiated neuronal damage, the present study focused on involvement of reactive oxygen species, protein kinase C (PKC), and glutamate receptors. Exposure of cerebellar granule cells to TMT (0.01-0.1 microM) produced primarily apoptosis, but higher concentrations were associated with cellular lactate dehydrogenase efflux and necrosis. TMT increased generation of cellular reactive oxygen species, which was inhibited by either L-NAME (inhibitor of nitric oxide synthase, NOS) or catalase, indicating that both NO and H(2)O(2) are formed on TMT exposure. Since chelerythrine (selective PKC inhibitor) also inhibited oxidative species generation, PKC appears to play a significant role in TMT-induced oxidative stress. The metabotropic glutamate receptor antagonist, MCPG, (but not MK-801) prevented oxidative species generation, indicating significant involvement of metabotropic receptors (but not NMDA receptors) in TMT-induced oxidative stress. NOS involvement in the action of TMT was confirmed through measurement of nitrite, which increased concentration dependently. Nitrite accumulation was blocked by L-NAME, chelerythrine, or MCPG, showing that NO is generated by TMT and that associated changes in NOS are regulated by a PKC-mediated mechanism. Oxidative damage by TMT was demonstrated by detection of elevated malondialdehyde levels. It was concluded that low concentrations of TMT (0.01-0.1 microM) cause apoptotic cell death in which oxidative signaling is an important event. Higher concentrations of TMT initiate necrotic death, which involves both an oxidative and a non-oxidative component. TMT-induced necrosis but not apoptosis in granule cells is mediated by glutamate receptors.

Curcumin (diferuoyl methane) from turmeric is a well-known biologically active compound. It has been shown to ameliorate oxidative stress and it is considered to be a potent cancer chemopreventive agent. In our previous study the antioxidative effects of curcumin in cadmium exposed animals were demonstrated. Also manganese exerts protective effects in experimental cadmium intoxication. The present study examined the ability of the manganese complex of curcumin (Mn-curcumin) and curcumin to protect against oxidative damage and changes in trace element status in cadmium-intoxicated male mice. Curcumin or Mn-curcumin were administered at equimolar doses (0.14 mmol/kg b.w.) for 3 days, by gastric gavages, dispersed in methylcellulose. One hour after the last dose of antioxidants, cadmium chloride (33 micromol/kg) was administered subcutaneously. Both curcumin and Mn-curcumin prevented the increase of hepatic lipid peroxidation -- expressed as MDA level, induced by cadmium intoxication and attenuated the Cd-induced decrease of hepatic GSH level. No change in hepatic glutathione peroxidase or catalase activities was found in Cd-exposed mice. A decreased GSH-Px activity was measured in curcumin and Mn-curcumin alone treated mice. Neither curcumin nor Mn-curcumin treatment influenced cadmium distribution in the tissues and did not correct the changes in the balance of essential elements caused by Cd-treatment. The treatment with Mn-curcumin increased the Fe and Mn content in the kidneys of both control and Cd-treated mice and Fe and Cu content in the brain of control mice. In conclusion, regarding the antioxidative action, introducing manganese into the curcumin molecule does not potentiate the studied effects of curcumin.

Oxidative tissue damage is considered an early sign of cadmium (Cd) toxicity and has been linked with carcinogenesis. Manganese(II)-at low doses, was found to act as a potent antioxidant against oxidative stress in different in vitro systems producing lipid peroxidation conditions. The present study investigates in vivo antioxidant effects of Mn2+ pretreatment in acute Cd intoxication with regard to lipid peroxidation, antioxidant defense system and cadmium distribution in the tissues of mice. Four groups of male mice (n=7–8) were used: Cd group was injected sc a single dose of CdCl2 · 2½ H2O · (7 mg/kg b.w.); Cd+Mn group was treated ip with MnCl2 · 4H2O (20 mg/kg b.w.) 24 hours before Cd intoxication; Mn group received manganese treatment only; Control group received saline only. Twenty-four hours after Cd intoxication an increased lipid peroxidation (p<0.05), depleted GSH level (p<0.01), increased activity of GSH-Px (p<0.05) and inhibited CAT activity (p<0.01) were found in Cd-treated group compared to controls. Manganese(II) pre-treatment either completely prevented (LP, GSH, GSH-Px) or significantly attenuated (CAT) these changes. Manganese(II) treatment alone decreased LP, enhanced hepatic GSH level and had no effect on antioxidant enzymes compared to control group. A significant increase of Cd concentration in the liver and decreased Cd concentration in the kidneys and testes were found in Cd+Mn treated mice compared to Cd-only treated group. The effect of manganese may result from a different metallothionein induction in particular organs. Manganese(II) pretreatment attenuated the interference of cadmium with Ca homeostasis, the alteration in Zn and Cu levels remained mostly unaffected.