Mechanism Based Therapeutic Strategies to Target Mitochondrial Stress and Endoplasmic Reticulum Stress in Rodent Stroke Models

Ischemic stroke is a major cause of morbidity and mortality in developed countries. Brain tissue damage in stroke arises from excessive release of excitatory neurotransmitters and results in mitochondrial dysfunction as well as cell death from apoptosis and endoplasmic reticulum (ER) stress responses. We have investigated the capacity of key neuroprotective pharmaceutical agents that include the disulfiram metabolite DETC-MeSO, the cytokine G-CSF and the amino acid taurine, to elicit pro-survival responses in rodent models of cerebral ischemia. We determined an important role for DETC-MeSO, G-CSF and taurine in selectively inhibiting different combinations of ER stress pathways in parallel with eliciting a decrease in infarct size in the rat middle cerebral artery occlusion (MCAO) model. Importantly each agent administered individually elicited potent pro-survival responses. Furthermore, combinations of taurine plus G-CSF or taurine plus DETC-MESO resulted in strong protection even when the agents were employed at low doses compared to the respective standard drug doses. Our ongoing studies on G-CSF treatment using the mouse bilateral carotid artery occlusion model (BCAO) of global ischemia point to major protection against ischemic damage that is related to regulation of specific ER stress pathways in addition to modulation of expression of key mitochondrial markers including Drp1 and Opa1. In summary, our studies indicate that DETC-MeSO, G-CSF and taurine each individually decreases ischemic damage in brain through acting on key ER and mitochondrial signaling pathways and that drug combinations employing these agents at low concentrations are capable of acting synergistically to successfully elicit ischemic brain protection.