title: Mode of action of S-methyl-N, N-diethylthiocarbamate sulfoxide (DETC-MeSO) as a novel therapy for stroke in a rat model.
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.
authors.affiliation: Department of Biomedical Sciences, Charles and Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, 33431, USA, pgharibani@gmail.com.
authors.forename: Payam
authors.initials: P
authors.lastname: Mohammad-Gharibani
authors.forename: Jigar
authors.initials: J
authors.lastname: Modi
authors.forename: Janet
authors.initials: J
authors.lastname: Menzie
authors.forename: Rafaella
authors.initials: R
authors.lastname: Genova
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ma
authors.forename: Rui
authors.initials: R
authors.lastname: Tao
authors.forename: Howard
authors.initials: H
authors.lastname: Prentice
authors.forename: Jang-Yen
authors.initials: JY
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy*; D013454:Sulfoxides / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; C557567:S-methyl-N,N-diethyldithiocarbamoyl sulfoxide; D013454:Sulfoxides