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Metallothionein‐III Prevents Glutamate and Nitric Oxide Neurotoxicity in Primary Cultures of Cerebellar Neurons

Abstract : Metallothionein (MT)‐III, a member of the MT family of metal‐binding proteins, is mainly expressed in the CNS and is abundant in glutamatergic neurons. Results in genetically altered mice indicate that MT‐III may play neuroprotective roles in the brain, but the mechanisms through which this protein functions have not been elucidated. The aim of this work was to assess whether MT‐III is able to prevent glutamate neurotoxicity and to identify the step of the neurotoxic process interfered with by MT‐III. Glutamate neurotoxicity in cerebellar neurons in culture is mediated by excessive activation of glutamate receptors, increased intracellular calcium, and increased nitric oxide. It is shown that MT‐III prevented glutamate‐ and nitric oxide‐induced neurotoxicity in a dose‐dependent manner, with nearly complete protection at 0.3‐1 μg/ml. MT‐III did not prevent the glutamate‐induced rise of intracellular calcium level but reduced significantly the nitric oxide‐induced formation of cyclic GMP. Circular dichroism analysis revealed that nitric oxide triggers the release of the metals coordinated to the cysteine residues of MT‐III, indicative of the SCys‐nitrosylation of the protein. Therefore, the present results indicate that MT‐III can quench pathological levels of nitric oxide, thus preventing glutamate and nitric oxide neurotoxicity.