Abstract T P239: Therapeutic Efficacy and Pharmacological Mechanisms of SP-8203 for Treatment of Cerebral Ischemia

In cerebral ischemia, neurons and glia are deteriorated by various mechanisms including excitotoxicity, oxidative stress and inflammatory responses. Thus, pharmacological blockade of multiple cytotoxic pathways would be a therapeutic strategy for the treatment of ischemic injury. We recently identified a novel multi-potent neuroprotectant SP-8203. Pharmacological efficacy and action mechanism of SP-8203 were evaluated in rat transient middle cerebral artery occlusion (MCAO). Post-ischemic treatment (i.v.) of SP-8203 reduced cerebral ischemic injury in a dose-dependent manner (0.03 ~ 10 mg/kg) and at clinically relevant therapeutic time window (up to 12 h after ischemia onset). Similar efficacy was also obtained in beagle dogs subjected to permanent MCAO. Although it did not ameliorate the excitotoxicity, SP-8203 markedly reduced ischemia-evoked oxidative stress via up-regulation of anti-oxidant enzymes, specifically Mn-SOD and Cu/Zn-SOD, but not catalase and glutathione reductase. SP-8203 also reduced the infiltration of ED-1-immunopositive monocytes and MPO-positive neutrophils into ischemic brain lesions of rats. Moreover, SP-8203 significantly reduced the release of pro-inflammatory cytokines/chemokines (e.g. IL-1beta, TNF-alpha, MCP-1) and also the expression of iNOS and resultant formation of nitrotyrosine. Early (3 h) thrombolysis with tPA restored perfusion and reduced infarction in embolic rat models. However, late 6-h tPA did not decrease infarction, but instead increased intracerebral hemorrhage and mortality. Interestingly, SP-8203 treatment at 1.5 h before late (6 h) tPA infusion markedly reduced tPA-evoked cerebral hemorrhage and mortality. Blood levels of MMPs were significantly correlated with the changes of hemorrhage and mortality. Taken together, SP-8203 has multiple neuroprotective activities in cerebral ischemia: up-regulation of anti-oxidant enzymes, reduction of inflammatory cells recruitment, and suppression of anti-inflammatory cytokines/chemokines and MMP expression. Thanks to the multiple neuroprotective mechanisms, SP-8203 could be a promising drug candidate for stroke treatment, especially in combination of tPA by extending therapeutic time window.