摘要 T P239：SP-8203治疗脑缺血的疗效及药理机制,Stroke

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摘要 T P239：SP-8203治疗脑缺血的疗效及药理机制
Stroke ( IF 7.8 ) Pub Date : 2015-02-01 , DOI: 10.1161/str.46.suppl_1.tp239
Won-Ki Kim ₁ , Chung Ju ₁ , Angela M. A. A Jalin ₁ , Jei-Man Ryu ₂ , Il-Hwan Cho ₂ , Won-Seok Kim ₂ , Byung-Su Kim ₂ , Yong-Hyun Lee ₂ , Eun-Bang Lee ₃

Affiliation

在脑缺血中，神经元和神经胶质细胞因兴奋性毒性、氧化应激和炎症反应等多种机制而退化。因此，多种细胞毒性途径的药理学阻断将是治疗缺血性损伤的一种治疗策略。我们最近发现了一种新型的多效神经保护剂 SP-8203。评价 SP-8203 在大鼠短暂性大脑中动脉闭塞 (MCAO) 中的药理功效和作用机制。SP-8203 的缺血后治疗 (iv) 以剂量依赖性方式 (0.03 ~ 10 mg/kg) 和临床相关治疗时间窗 (缺血发作后长达 12 小时) 减少脑缺血性损伤。在遭受永久性 MCAO 的比格犬中也获得了类似的功效。虽然它并没有改善兴奋性毒性，SP-8203 通过上调抗氧化酶，特别是 Mn-SOD 和 Cu/Zn-SOD，而不是过氧化氢酶和谷胱甘肽还原酶，显着降低缺血诱发的氧化应激。SP-8203 还减少了 ED-1 免疫阳性单核细胞和 MPO 阳性中性粒细胞在大鼠缺血性脑损伤中的浸润。此外，SP-8203 显着降低了促炎细胞因子/趋化因子（例如 IL-1beta、TNF-alpha、MCP-1）的释放以及 iNOS 的表达和由此产生的硝基酪氨酸的形成。在栓塞大鼠模型中，用 tPA 进行的早期（3 小时）溶栓恢复了灌注并减少了梗塞。然而，晚期 6 小时 tPA 并未减少梗塞，反而增加了脑出血和死亡率。有趣的是，SP-8203 处理 1。晚期（6 小时）tPA 输注前 5 小时显着降低了 tPA 诱发的脑出血和死亡率。血中MMPs水平与出血和死亡率的变化显着相关。总之，SP-8203 在脑缺血中具有多种神经保护活性：抗氧化酶的上调、炎症细胞募集的减少以及抗炎细胞因子/趋化因子和 MMP 表达的抑制。由于多种神经保护机制，SP-8203 可能成为治疗中风的有前途的候选药物，特别是通过延长治疗时间窗与 tPA 联合使用。减少炎症细胞募集，抑制抗炎细胞因子/趋化因子和 MMP 表达。由于多种神经保护机制，SP-8203 可能成为治疗中风的有前途的候选药物，特别是通过延长治疗时间窗与 tPA 联合使用。减少炎症细胞募集，抑制抗炎细胞因子/趋化因子和 MMP 表达。由于多种神经保护机制，SP-8203 可能成为治疗中风的有前途的候选药物，特别是通过延长治疗时间窗与 tPA 联合使用。

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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.

更新日期：2015-02-01

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