Rich Megan C, Keene Chesleigh N, Neher Miriam D, Johnson Krista, Yu Zhao-Xue, Ganivet Antoine, Holers V Michael, Stahel Philip F
Department of Orthopaedic Surgery, Denver Health Medical Center and University of Colorado School of Medicine, Denver, CO 80204, USA.
Alexion Pharmaceuticals, Cheshire, CT 06410, USA.
Neurosci Lett. 2016 Mar 23;617:188-94. doi: 10.1016/j.neulet.2016.02.025. Epub 2016 Feb 15.
Intracerebral complement activation after severe traumatic brain injury (TBI) leads to a cascade of neuroinflammatory pathological sequelae that propagate host-mediated secondary brain injury and adverse outcomes. There are currently no specific pharmacological agents on the market to prevent or mitigate the development of secondary cerebral insults after TBI. A novel chimeric CR2-fH compound (mTT30) provides targeted inhibition of the alternative complement pathway at the site of tissue injury. This experimental study was designed to test the neuroprotective effects of mTT30 in a mouse model of closed head injury. The administration of 500 μg mTT30 i.v. at 1 h, 4 h and 24 h after head injury attenuated complement C3 deposition in injured brains, reduced the extent of neuronal cell death, and decreased post-injury microglial activation, compared to vehicle-injected placebo controls. These data imply that site-targeted alternative pathway complement inhibition may represent a new promising therapeutic avenue for the future management of severe TBI.
严重创伤性脑损伤（TBI）后，脑内补体激活会引发一系列神经炎症性病理后遗症，从而导致宿主介导的继发性脑损伤和不良后果。目前市面上尚无特异性药物可预防或减轻TBI后继发性脑损伤的发展。一种新型嵌合CR2-fH化合物（mTT30）可在组织损伤部位对替代补体途径进行靶向抑制。本实验研究旨在测试mTT30在闭合性颅脑损伤小鼠模型中的神经保护作用。与注射赋形剂的安慰剂对照组相比，在头部受伤后1小时、4小时和24小时静脉注射500μg mTT30可减轻受伤脑内补体C3沉积，减少神经元细胞死亡程度，并降低损伤后小胶质细胞的激活。这些数据表明，针对替代途径的补体抑制可能是未来重度TBI治疗的一个新的有前景的治疗途径。
