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

Payam Mohammadgharibani, Jigar Modi, Janet Menzie, Rafaella Genova, Zhiyuan Ma, Rui Tao, Howard Prentice, Jang Yen Wu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)655-672
Number of pages18
JournalMolecular Neurobiology
Volume50
Issue number2
DOIs
StatePublished - Oct 2 2014
Externally publishedYes

Fingerprint

sulfoxide
Stroke
Apoptosis Regulatory Proteins
Endoplasmic Reticulum Stress
Therapeutics
Middle Cerebral Artery Infarction
Microdialysis
Heat-Shock Proteins
HSP27 Heat-Shock Proteins
Apoptosis
Disulfiram
S-methyl N,N-diethylthiolcarbamate sulfoxide
Neurons
Corpus Striatum
Brain Hypoxia
Spectrin
Excitatory Amino Acid Antagonists
Gliosis

Keywords

  • DETC-MeSO
  • Endoplasmic reticulum stress
  • Excitotoxicity
  • Neuroprotection
  • Primary cortical neuronal culture
  • Stroke

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Mode of Action of S-Methyl-N, N-Diethylthiocarbamate Sulfoxide (DETC-MeSO) as a Novel Therapy for Stroke in a Rat Model. / Mohammadgharibani, Payam; Modi, Jigar; Menzie, Janet; Genova, Rafaella; Ma, Zhiyuan; Tao, Rui; Prentice, Howard; Wu, Jang Yen.

In: Molecular Neurobiology, Vol. 50, No. 2, 02.10.2014, p. 655-672.

Research output: Contribution to journalArticle

Mohammadgharibani, Payam ; Modi, Jigar ; Menzie, Janet ; Genova, Rafaella ; Ma, Zhiyuan ; Tao, Rui ; Prentice, Howard ; Wu, Jang Yen. / Mode of Action of S-Methyl-N, N-Diethylthiocarbamate Sulfoxide (DETC-MeSO) as a Novel Therapy for Stroke in a Rat Model. In: Molecular Neurobiology. 2014 ; Vol. 50, No. 2. pp. 655-672.
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AU - Mohammadgharibani, Payam

AU - Modi, Jigar

AU - Menzie, Janet

AU - Genova, Rafaella

AU - Ma, Zhiyuan

AU - Tao, Rui

AU - Prentice, Howard

AU - Wu, Jang Yen

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