Antioxidant compounds and Ca2+ pathway blockers differentially protect against methylmercury and mercuric chloride neurotoxicity

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Abstract
The effects of the environmental contaminants methylmercury (MeHg) and inorganic mercury (HgCl2) on cell viability, intracellular calcium concentration ([Ca2+]i), and reactive oxygen species (ROS) generation were studied in rat cerebellar granule neuron cultures using fluorescent methods. MeHg exhibited an LC50 (2.47 μM) tenfold lower than that of HgCl2 (26.40 μM). To study the involvement of oxidative stress and Ca2+ homeostasis disruption in mercury‐induced cytotoxicity, we tested the neuroprotective effects of several agents that selectively interfere with these mechanisms. After a 24 hr exposure, the cytotoxic effect of both mercury compounds was reduced by thapsigargin, an inhibitor of endoplasmic reticulum Ca2+‐ATPase; the Ca2+ channel blocker flunarizine; and the Na+/Ca2+ exchanger blocker benzamil. All these compounds decreased the mercury‐mediated [Ca2+]i rise. These results indicate that Ca2+ influx through Ca2+ channels and the Na+/Ca2+ exchanger and Ca2+ mobilization from the endoplasmic reticulum are involved in mercury‐mediated cytotoxicity. The antioxidants probucol and propyl gallate reduced the HgCl2 toxicity. Probucol and vitamin E partially inhibited the MeHg toxicity after a 24 hr period, whereas propyl gallate completely prevented this effect. Probucol slightly reduced ROS generation in methylmercury‐exposed cultures and decreased mercury‐mediated rise of [Ca2+]i. Propyl gallate abolished ROS generation and partially inhibited the increase of [Ca2+]i induced by both mercury compounds. Propyl gallate also protected human cerebral cortical neuron cultures from the MeHg effect even after 72 hr of MeHg exposure, thus showing a long‐lasting effect. Our data suggest that disruption of redox equilibrium and Ca2+ homeostasis contribute equally to HgCl2‐mediated toxicity, whereas oxidative stress is the main cause of MeHg neurotoxicity. J. Neurosci. Res. 66:135–145, 2001.
Funding Information
  • Spanish Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS) (00/1094)
  • Comissió Interdepartamental de Recerca i Innovació Tecnològica, Generalitat de Catalunya (CIRIT) (SGR00047)

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