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Mode of Action of S-Methyl-N, N-Diethylthiocarbamate Sulfoxide (DETC-MeSO) as a Novel Therapy for Stroke in a Rat Model

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Abstract

One approach for protecting neurons from excitotoxic damage in stroke is to attenuate receptor activity with specific antagonists. S-Methyl-N, N-diethylthiocarbamate sulfoxide (DETC-MeSO), the active metabolite of disulfiram, has been shown to be a partial antagonist of glutamate receptors and effective in reducing seizure. First, we investigated neuroprotective effect of DETC-MeSO on primary cortical neuronal culture under hypoxia/reoxygenation condition in vitro. Then, DETC-MeSO was administered subcutaneously for 4 and 8 days with the first injection occurring 1 h before or 24 h after reperfusion in the rat middle cerebral artery occlusion stroke model. Rats were subjected to the neuroscore test, and the brain was analyzed for infarct size. Monitoring neurotransmitter release was carried out by microdialysis. Heat shock proteins, key proteins involved in apoptosis and endoplasmic reticulum (ER) stress, were analyzed by immunoblotting. DETC-MeSO greatly reduced both cell death following hypoxia/reoxygenation and brain infarct size. It improved performance on the neuroscore test and attenuated proteolysis of αII-spectrin. The level of pro-apoptotic proteins declined, and anti-apoptotic and HSP27 protein expressions were markedly increased. Levels of the ER stress protein markers p-PERK, p-eIF2α, ATF4, JNK, XBP-1, GADD34, and CHOP significantly declined after DETC-MeSO administration. Microdialysis data showed that DETC-MeSO increased high potassium-induced striatal dopamine release indicating that more neurons were protected and survived under ischemic insult in the presence of DETC-MeSO. We also showed that DETC-MeSO can prevent gliosis. DETC-MeSO elicits neuroprotection through the preservation of ER resulting in reduction of apoptosis by increase of anti-apoptotic proteins and decrease of pro-apoptotic proteins.

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Acknowledgments

This research was supported in part by grant 09KW-11, Department of Health, State of Florida.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Charles and Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA

    Payam Mohammad-Gharibani, Jigar Modi, Janet Menzie, Rafaella Genova, Zhiyuan Ma, Rui Tao, Howard Prentice & Jang-Yen Wu

  2. Program in Integrative Biology, Florida Atlantic University, Boca Raton, FL, 33431, USA

    Rui Tao, Howard Prentice & Jang-Yen Wu

  3. Center of Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL, 33431, USA

    Jigar Modi, Howard Prentice & Jang-Yen Wu

  4. China Medical University Hospital, China Medical University, Taichung, 40447, Taiwan

    Jang-Yen Wu

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  1. Payam Mohammad-Gharibani
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Mohammad-Gharibani, P., Modi, J., Menzie, J. et al. Mode of Action of S-Methyl-N, N-Diethylthiocarbamate Sulfoxide (DETC-MeSO) as a Novel Therapy for Stroke in a Rat Model. Mol Neurobiol 50, 655–672 (2014). https://doi.org/10.1007/s12035-014-8658-0

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