Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury.
Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury.
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DOI：
10.1007/s12975-017-0532-8
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发表时间：
2017-08
影响因子：
6.9
通讯作者：
Stenzel-Poore MP
中科院分区：
文献类型：
--
作者：
Bahjat FR;Alexander West G;Kohama SG;Glynn C;Urbanski HF;Hobbs TR;Earl E;Stevens SL;Stenzel-Poore MP
脑缺血再灌注性损伤可由医源性继发于救命手术引起。这些患者的预防性治疗为终生并发症提供了一种很有希望的预防方法。我们推测，CpG寡核苷酸(ODN)可以在最小限度释放促炎细胞因子的情况下，对脑缺血损伤提供强有力的预先保护，使其成为进一步临床开发的理想候选者。采用小鼠和非人灵长类动物脑缺血损伤模型，检测A型CpG ODN是否具有预防性保护作用，它能诱导最小的全身炎症细胞因子反应。通过组织学染色观察小鼠的损伤程度。在NHP中，根据T2加权磁共振图像在闭塞后2天和7天评估损伤，并每天对神经和运动缺陷进行分类。采用种属特异性Luminex法测定血浆细胞因子水平。预防性给予A-型CpG ODN在小鼠脑缺血损伤中提供了强有力的保护，全身炎症最小。D192935是一种人类优化的A型CpG ODN的混合物，用D192935治疗的猕猴在缺血损伤后梗死较小，神经和运动障碍明显减少。我们的研究结果证明了D192935作为脑缺血损伤风险患者预防性治疗的潜力。
Ischemia-reperfusion brain injury can be iatrogenically-induced secondary to life-saving procedures. Prophylactic treatment of these patients offers a promising prevention for life-long complications. We postulate that a CpG oligodeoxynucleotide (ODN) can provide robust antecedent protection against cerebral ischemic injury with minimal release of pro-inflammatory cytokines, making it an ideal candidate for further clinical development. Mouse and nonhuman primate (NHP) models of cerebral ischemic injury were used to test whether an A-type CpG ODN, which induces minimal systemic inflammatory cytokine responses, can provide prophylactic protection. Extent of injury in the mouse was measured by histological staining of live tissue. In the NHP, injury was assessed 2 and 7 days post-occlusion from T2-weighted magnetic resonance images and neurological and motor deficits were cataloged daily. Plasma cytokine levels were measured using species specific Luminex assays. Prophylactic administration of an A-type CpG ODN provided robust protection against cerebral ischemic injury in the mouse with minimal systemic inflammation. Rhesus macaques treated with D192935, a mixture of human optimized A-type CpG ODNs, had smaller infarcts and demonstrated significantly less neurological and motor deficits following ischemic injury. Our findings demonstrate the translational potential of D19293 5 as a prophylactic treatment for patients at risk of cerebral ischemic injury.