Eliachar Research Laboratory, Galilee Medical Center, Nahariya 2210001, Israel.
Galilee Medical Center, Department of Neurosurgery, Nahariya 2210001, Israel.
Int J Mol Sci. 2021 Nov 28;22(23):12881. doi: 10.3390/ijms222312881.
The opening of the mitochondrial permeability transition pore (mPTP) has emerged as a pivotal event following traumatic brain injury (TBI). Evidence showing the impact of the translocator protein (TSPO) over mPTP activity has prompted several studies exploring the effect of TSPO ligands, including etifoxine, on the outcome of traumatic brain injury (TBI). Mitochondrial respiration was assessed by respirometry in isolated rat brain mitochondria (RBM) by measurements of oxidative phosphorylation capacity (OXPHOS). The addition of calcium to RBM was used to induce mitochondrial injury and resulted in significant OXPHOS reduction that could be reversed by preincubation of RBM with etifoxine. Sensorimotor and cognitive functions were assessed following controlled cortical impact and compared in vehicle and etifoxine-treated animals. There was no difference between the vehicle and etifoxine groups for sensorimotor functions as assessed by rotarod. In contrast, etifoxine resulted in a significant improvement of cognitive functions expressed by faster recovery in Morris water maze testing. The present findings show a significant neuroprotective effect of etifoxine in TBI through restoration of oxidative phosphorylation capacity associated with improved behavioral and cognitive outcomes. Since etifoxine is a registered drug used in common clinical practice, implementation in a phase II study may represent a reasonable step forward.
线粒体通透性转换孔（mPTP）的开放已成为创伤性脑损伤（TBI）后的一个关键事件。证据表明，转位蛋白（TSPO）对 mPTP 活性的影响促使了几项研究探索 TSPO 配体（包括乙非他命）对创伤性脑损伤（TBI）结果的影响。通过测量氧化磷酸化能力（OXPHOS），采用呼吸计在分离的大鼠脑线粒体（RBM）中评估线粒体呼吸。向 RBM 中添加钙可诱导线粒体损伤，并导致 OXPHOS 显著减少，而 RBM 与乙非他命预孵育可逆转这种减少。在皮质控制冲击后评估感觉运动和认知功能，并在载体和乙非他命处理的动物中进行比较。在旋转棒测试中，载体组和乙非他命组的感觉运动功能没有差异。相比之下，乙非他命可通过在 Morris 水迷宫测试中更快的恢复来显著改善认知功能。本研究结果表明，乙非他命在 TBI 中具有显著的神经保护作用，这与氧化磷酸化能力的恢复以及行为和认知结果的改善有关。由于乙非他命是一种在常见临床实践中使用的注册药物，在 II 期研究中实施可能是一个合理的步骤。
