PDF(Pubmed)
Abstract：
Stroke results in neuronal cell death, which causes long-term disabilities in adults. Treatment options are limited and rely on a narrow window of opportunity. Apoptosis inhibitors demonstrate efficacy in improving neuronal cell survival in animal models of stroke. However, many inhibitors non-specifically target apoptosis pathways and high doses are needed for treatment. We explored the use of a novel caspase-3/7 inhibitor, New World Laboratories (NWL) 283, with a lower IC50 than current caspase-3/7 inhibitors. We performed in vitro and in vivo assays to determine the efficacy of NWL283 in modulating cell death in a preclinical model of stroke. In vitro and in vivo assays show that NWL283 enhances cell survival of neural precursor cells. Delivery of NWL283 following stroke enhances endogenous NPC migration and leads to increased neurogenesis in the stroke-injured cortex. Furthermore, acute NWL283 administration is neuroprotective at the stroke injury site, decreasing neuronal cell death and reducing microglia activation. Coincident with NWL283 delivery for 8 days, stroke-injured mice exhibited improved functional outcomes that persisted following cessation of the drug. Therefore, we propose that NWL283 is a promising therapeutic warranting further investigation to enhance stroke recovery.
摘要：
中风导致神经元细胞死亡，导致成人长期残疾。治疗选择是有限的，并且依赖于狭窄的机会窗口。凋亡抑制剂在中风动物模型中显示出改善神经元细胞存活的功效。然而,许多抑制剂非特异性靶向凋亡途径,治疗需要高剂量.我们探索了一种新型caspase-3/7抑制剂的使用，新世界实验室(NWL)283,具有比目前的半胱天冬酶-3/7抑制剂更低的IC50。我们进行了体外和体内测定，以确定NWL283在中风临床前模型中调节细胞死亡的功效。体外和体内测定显示NWL283增强神经前体细胞的细胞存活。中风后NWL283的递送增强内源性NPC迁移并导致中风损伤的皮质中神经发生增加。此外，急性NWL283给药在中风损伤部位具有神经保护作用，减少神经元细胞死亡和减少小胶质细胞激活。与NWL283交付8天一致，卒中损伤小鼠的功能结局改善,停药后持续.因此,我们认为NWL283是一种有前景的治疗方法,值得进一步研究以提高卒中恢复.
