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Mechanism of okadaic acid‐induced neuronal death and the effect of estrogens
Author(s) -
Yi Kun Don,
Covey Douglas F.,
Simpkins James W.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05805.x
Subject(s) - neuroprotection , okadaic acid , glutamate receptor , protein kinase a , neurotoxicity , kinase , biochemistry , phosphatase , oxidative stress , chemistry , reactive oxygen species , pharmacology , biology , microbiology and biotechnology , phosphorylation , toxicity , receptor , organic chemistry
Serine/threonine protein phosphatases are important mediators of general cellular function as well as neurodegenerative processes. We have previously shown inhibition of protein phosphatases to be as neurotoxic as glutamate‐induced neuronal death but resistant to neuroprotection by estrogens. In this study, the mechanism by which phosphatase inhibition via okadaic acid (OA) induced neurotoxicity is explored. Neurons were exposed to OA or glutamate in the presence or absence of various protein kinases inhibitors, and/or one of four estrogens. Both OA and glutamate induced cell death via increased reactive oxygen species, protein carbonylation, lipid peroxidation, caspase‐3 activity, and mitochondrial dysfunction. All estrogens attenuated glutamate‐mediated responses, but not OA‐induced responses. In addition, inhibition of protein kinase C and mitogen‐activated protein kinase pathway was neuroprotective against glutamate but not OA toxicity. Interestingly, inhibition of mitogen‐activated protein kinase pathway with PD98096 or U0126 caused a decrease in reactive oxygen species production suggesting that activation of ERK1/2 could further exacerbate the oxidative stress caused by glutamate‐induced toxicity; however, these inhibitors had no effect on OA‐induced toxicity. Collectively, these results indicate that both glutamate and OA neurotoxicities are mediated by persistent activation of ERK1/2 and/or protein kinase C and a resulting oxidative stress, and that protein phosphatase activity is an important and necessary aspect of estrogen‐mediated neuroprotection.