NINDS Cooperative Program in Translational Research

(前提)其对急性缺血的反应从诱导细胞损伤的信号级联到诱导 神经保护通路(耐受性)。这种内源性神经保护通过Toll样发生 受体(TLR)信号，将中风后的炎症(伤害性)反应重新编程为抗炎 (神经保护性)反应。我们提供首选的激动剂(CpG ODN和咪喹莫特-ImQ) TLR9和TLR7分别作为预防中风神经保护的先导化合物。虽然 已经产生了可靠的啮齿动物数据，过去和最近的翻译失败需要额外的临床前研究 评估。因此，我们开发了一种新的灵长类中风模型来评估推测的中风 并提议对我们最近发现的神经保护剂进行严格的试验，以 建立必要的药效和药代动力学数据。因此，我们的初步研究支持新的稳健 高危中风患者的神经保护策略将在非人类灵长类动物中进一步测试，方法是： 目的1.确定TLR9(K-和D-Mix CpG ODN)实现神经保护作用的最佳剂量 和TLR7(ImQ)候选药物作为皮质卒中NHP模型的预防治疗。 目的2.确定K-和D-Mix CpG ODN和ImQ AS神经保护作用的时间窗 皮质性卒中NHP模型中的预防性治疗。 目的3.确定CpG ODN(K和D混合物)和ImQ作为预防治疗的神经保护作用。 老年NHP的皮质卒中模型。 目的4.测定CpG ODN(K-和D-Mix)重复给药的神经保护作用 在NHP皮质卒中模型中，IMQ作为预防性治疗。 目的5.确定最佳CpG ODN(K-和D-Mix)和ImQ AS的神经保护效果 女性NHP皮质性卒中模型的预防性治疗。 目的6.测定CpG ODN(K-和D-Mix)和ImQ的药代动力学和毒性 中风治疗学。 目标7.提交IND申请，根据疗效、药代动力学和 毒性特征。

(precondition) its response to acute ischemia from that of induced cell injury signaling cascades to induction of neuroprotective pathways (tolerance). Such endogenous neuroprotection occurs through Toll Like Receptor (TLR) signaling which reprograms an inflammatory (injurious) response to stroke into an antiinflammatory (neuroprotective) response. We offer the preferred agonists (CpG ODNs and imiquimod - IMQ) of TLR 9 and 7 respectively as lead compounds for prophylactic neuroprotection against stroke. Although robust rodent data have been produced, past and recent translational failures require additional preclinical evaluation. Accordingly, we have developed a new primate stroke model for assessment of putative pharmacotherapeutics and propose to perform rigorous trials of our recently discovered neuroprotectants to establish essential effacy and pharmacokinetic data. Thus our preliminary studies support new robust neuroprotective strategies for high-risk stroke patients to be further tested in the non-human primate via: Aim 1. Determine the optimal dose to achieve neuroprotective efficacy for TLR9 (K- and D-mix CpG ODNs) and TLR7 (IMQ) candidate drugs as prophylactic therapy in a NHP model of cortical stroke. Aim 2. Determine the time window of neuroprotective efficacy for K- and D-mix CpG ODNs and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 3. Determine neuroprotective efficacy CpG ODN (K and D mix) and IMQ as prophylactic therapy in a model of cortical stroke in the aged NHP. Aim 4. Determine the neuroprotective efficacy of repeated administration of CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 5. Determine the neuroprotective efficacy of the optimal CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a model of cortical stroke in female NHPs. Aim 6. Determine pharmacokinetic and toxicity profiles of CpG ODN (K- and D-mix) and IMQ as potential stroke therapeutics. Aim 7. Submit an IND application for the optimal TLR candidate based on efficacy, pharmacokinetics and toxicity profiles.