Excessive zinc ion (Zn²⁺) release is induced in pathological situations and causes neuronal cell death. Previously, we have reported that copper ions (Cu²⁺) markedly exacerbated Zn²⁺-induced neuronal cell death by potentiating oxidative stress, the endoplasmic reticulum (ER) stress response, and the activation of the c-Jun amino-terminal kinase (JNK) signaling pathway. In contrast, selenium (Se), an essential trace element, and amino acids containing selenium (such as seleno-l-methionine) have been reported to inhibit stress-induced neuronal cell death and oxidative stress. Thus, we investigated the effect of seleno-l-methionine on Cu²⁺/Zn²⁺-induced neuronal cell death in GT1-7 cells. Seleno-l-methionine treatment clearly restored the Cu²⁺/Zn²⁺-induced decrease in the viable cell number and attenuated the Cu²⁺/Zn²⁺-induced cytotoxicity. Accordingly, the levels of ER stress-related factors (especially, CHOP and GADD34) and of phosphorylated JNK increased upon CuCl₂ and ZnCl₂ co-treatment, whereas pre-treatment with seleno-l-methionine significantly suppressed these upregulations. Analysis of reactive oxygen species (ROS) as upstream factors of these pathways revealed that Cu²⁺/Zn²⁺-induced ROS production was clearly suppressed by seleno-l-methionine treatment. Finally, we found that seleno-l-methionine induced the antioxidative protein, glutathione peroxidase. Taken together, our findings suggest that seleno-l-methionine suppresses Cu²⁺/Zn²⁺-induced neuronal cell death and oxidative stress via induction of glutathione peroxidase. Thus, we think that seleno-l-methionine may help prevent refractory neurological diseases.

Saki Okudomi

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