Global Summit on Stroke
Florida Atlantic University, USA
Title: Novel strategies for stroke therapy based on targeting of mitochondrial dysfunction and ER stress signaling pathways
Biography: Howard Prentice
There is a major need for new stroke therapies, and current treatments involving tissue plasminogen activator (tPA) are dependent\\r\\nupon administration within small time-window aft er stroke onset. We have employed the neuroprotective agents taurine and\\r\\nS-Methyl-N, N-diethylthiocarbamate (DETC-MeSO) either individually, or as part of particular combination therapies, to elicit\\r\\nneuroprotection in a transient focal ischemia rat stroke model. Individually, taurine can protect neurons against ischemia through\\r\\npreventing calcium overload and through inhibiting pro-apoptotic processes. In our studies on endoplasmic reticulum (ER) stress\\r\\npathways, we have demonstrated that taurine elicits neuroprotection by inhibiting two ER stress pathways, namely ATF6 and\\r\\nIRE-1 pathways, without altering the contribution of the PERK pathway. DETC-MeSO, the active metabolite of disulfi ram, is\\r\\na partial antagonist of glutamate receptors and was previously shown to be eff ective in reducing seizures. In our stroke model,\\r\\nDETC-MeSO administered individually, protected through inhibiting ER stress markers including p-PERK, p-eIF2-alpha, XBP-1\\r\\nand CHOP. Using a multi-drug combination consisting of DETC-MeSO and the stem cell mobilizing agent granulocyte colony\\r\\nstimulating factor (G-CSF), in addition to the preconditioning agent sulindac, we found that infarct size was markedly decreased\\r\\nin the stroke model relative to sham controls. With administration of these agents prior to reperfusion, multidrug treatment was\\r\\nfound, at 4 days aft er the ischemic episode, to elicit decreases in GRP78, eIF-2-alpha and IRE-1, both in core and penumbra. Th e\\r\\nmulti-drug combination was highly eff ective at decreasing infarct size, either under conditions of prior administration, or with\\r\\nadministration of the drug combination 24 hours aft er reperfusion. Our novel therapeutic agents were found to decrease infarct\\r\\nsize, to elicit protection through decreasing levels of pro-apoptotic components and furthermore to diff erentially target specifi c\\r\\nER stress pathways.