Li Han-Dong, Li Minshu, Shi Elaine, Jin Wei-Na, Wood Kristofer, Gonzales Rayna, Liu Qiang
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
J Neuroinflammation. 2017 Jul 28;14(1):151. doi: 10.1186/s12974-017-0921-7.
Cerebral ischemia is a leading cause of death and disability with limited treatment options. Although inflammatory and immune responses participate in ischemic brain injury, the molecular regulators of neuroinflammation after ischemia remain to be defined. Translocator protein 18 kDa (TSPO) mainly localized to the mitochondrial outer membrane is predominantly expressed in glia within the central nervous system during inflammatory conditions. This study investigated the effect of a TSPO agonist, etifoxine, on neuroinflammation and brain injury after ischemia/reperfusion.
We used a mouse model of middle cerebral artery occlusion (MCAO) to examine the therapeutic potential and mechanisms of neuroprotection by etifoxine.
TSPO was upregulated in Iba1 or CD11bCD45 cells from mice subjected to MCAO and reperfusion. Etifoxine significantly attenuated neurodeficits and infarct volume after MCAO and reperfusion. The attenuation was pronounced in mice subjected to 30, 60, or 90 min MCAO. Etifoxine reduced production of pro-inflammatory factors in the ischemic brain. In addition, etifoxine treatment led to decreased expression of interleukin-1β, interleukin-6, tumor necrosis factor-α, and inducible nitric oxide synthase by microglia. Notably, the benefit of etifoxine against brain infarction was ablated in mice depleted of microglia using a colony-stimulating factor 1 receptor inhibitor.
These findings indicate that the TSPO agonist, etifoxine, reduces neuroinflammation and brain injury after ischemia/reperfusion. The therapeutic potential of targeting TSPO requires further investigations in ischemic stroke.
脑缺血是导致死亡和残疾的主要原因，治疗选择有限。尽管炎症和免疫反应参与缺血性脑损伤，但缺血后神经炎症的分子调节因子仍有待确定。18 kDa转位蛋白（TSPO）主要定位于线粒体外膜，在炎症状态下主要在中枢神经系统的神经胶质细胞中表达。本研究探讨了TSPO激动剂依替福辛对缺血/再灌注后神经炎症和脑损伤的影响。
我们使用大脑中动脉闭塞（MCAO）小鼠模型来研究依替福辛的治疗潜力和神经保护机制。
在接受MCAO和再灌注的小鼠的Iba1或CD11bCD45细胞中，TSPO上调。依替福辛显著减轻MCAO和再灌注后的神经功能缺损和梗死体积。在接受30、60或90分钟MCAO的小鼠中，这种减轻作用明显。依替福辛减少了缺血脑中促炎因子的产生。此外，依替福辛治疗导致小胶质细胞中白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α和诱导型一氧化氮合酶的表达降低。值得注意的是，使用集落刺激因子1受体抑制剂清除小胶质细胞的小鼠中，依替福辛对脑梗死的益处消失。
这些发现表明，TSPO激动剂依替福辛可减少缺血/再灌注后的神经炎症和脑损伤。靶向TSPO的治疗潜力在缺血性卒中中需要进一步研究。
