Probucol increases glutathione peroxidase-1 activity and displays long-lasting protection against methylmercury toxicity in cerebellar granule cells.
Methylmercury (MeHg) is an environmental neurotoxicant whose molecular mechanisms underlying toxicity remain elusive. Here, we investigated molecular events involved in MeHg-induced neurotoxicity in cultured cerebellar granule cells (CGCs) as well as potential protective strategies for such toxicity. Glutathione peroxidase, isozyme 1 (GPx-1) activity was significantly (p = 0.0017) decreased at 24 h before MeHg-induced neuronal death (day in vitro 4). This event was related to enhanced susceptibilities to hydrogen peroxide or tert-butyl peroxide and increased lipid peroxidation. However, intracellular calcium levels, glutamate uptake, and glutathione levels, as well as glutathione reductase and catalase activities, were not changed by MeHg exposure at this time point. Probucol (PB), a lipid-lowering drug, displayed a long-lasting protective effect against MeHg-induced neurotoxicity. The beneficial effects of PB were correlated with increased GPx-1 activity and decreased lipid peroxidation. The protection afforded by PB was significantly higher when compared to the antioxidants, ascorbic acid and trolox. In vitro studies with the purified GPx-1 proved that MeHg inhibits and PB activates the enzyme activity. Overexpression of GPx-1 prevented MeHg-induced neuronal death. These data indicate that (1) GPx-1 is an important molecular target involved in MeHg-induced neurotoxicity and (2) PB, which increases GPx-1 activity in CGCs, induces enduring protection against such toxicity. The results bring out new insights on the potential therapeutic strategies for poisonings to MeHg and other pathological conditions related to increased production and/or decreased detoxification of peroxides.
Farina
Marcelo
M
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, CSIC-IDIBAPS, Barcelona 08036, Spain. farina@ccb.ufsc.br
Campos
Francisco
F
Vendrell
Iolanda
I
Berenguer
Jordi
J
Barzi
Mercedes
M
Pons
Sebastián
S
Suñol
Cristina
C
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D015227:Lipid Peroxidation; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D011341:Probucol / Q000494:pharmacology*; D000094765:Glutathione Peroxidase GPX1
D000924:Anticholesteremic Agents; D000975:Antioxidants; D008767:Methylmercury Compounds; D002374:Catalase; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; D011341:Probucol; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse