Department of Neurosurgery, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Brain Res. 2012 Sep 7;1472:113-23. doi: 10.1016/j.brainres.2012.06.053. Epub 2012 Jul 11.
Cyclosporin A (CsA) has been demonstrated to be neuroprotective in ischemic and traumatic brain injuries by inhibiting mitochondrial permeability transition pore (mPTP) opening, thereby maintaining mitochondrial homeostasis and inhibiting pro-apoptotic protein release. The effects of CsA on early brain injury (EBI) after subarachnoid hemorrhage (SAH), however, have not been investigated. This study was designed to explore the effects of CsA on apoptotic signaling pathways and EBI after experimental SAH using four equal groups (n=36) of adult male SD rats, including the sham group, SAH+vehicle group, SAH+CsA2 group, and SAH+CsA10 group. The rat SAH model was induced by injection of 0.3ml non-heparinized arterial blood into the prechiasmatic cistern. In the SAH+CsA2 and SAH+CsA10 groups, a dose of 2mg/kg and 10mg/kg CsA was directly administered by intercarotid injection at 15min and again 24h after SAH induction. Cerebral tissue samples were extracted 48h after SAH. Increased expressions of Cytochrome C, apoptosis-inducing factor (AIF), and cleaved caspase-3 were observed in the cerebral cortex after SAH. Treatment with high dose (10mg/kg) CsA markedly decreased expressions of Cytochrome C, AIF, and cleaved caspase-3, and inhibited apoptosis pathways. Administration of CsA following SAH significantly ameliorated EBI, including cortical apoptosis, brain edema, blood-brain barrier (BBB) impairment, and neurobehavioral deficits. These findings suggest that early administration of CsA may ameliorate EBI and provide neuroprotection in the SAH model through potential mechanisms that include blockage of mPTP opening and inhibition of apoptotic cell death pathways.
环孢素 A（CsA）通过抑制线粒体通透性转换孔（mPTP）开放，从而维持线粒体稳态并抑制促凋亡蛋白释放，已被证明在缺血性和创伤性脑损伤中具有神经保护作用。然而，CsA 对蛛网膜下腔出血（SAH）后早期脑损伤（EBI）的影响尚未得到研究。本研究旨在通过四个相等的成年雄性 SD 大鼠组（每组 n=36），包括假手术组、SAH+载体组、SAH+CsA2 组和 SAH+CsA10 组，来探讨 CsA 对实验性 SAH 后凋亡信号通路和 EBI 的影响。通过向视交叉前池注射 0.3ml 非肝素化动脉血来诱导大鼠 SAH 模型。在 SAH+CsA2 和 SAH+CsA10 组中，在 SAH 诱导后 15min 和 24h 分别通过颈内动脉注射 2mg/kg 和 10mg/kg CsA。在 SAH 后 48h 提取脑组织样本。在 SAH 后大脑皮质中观察到细胞色素 C、凋亡诱导因子（AIF）和裂解的 caspase-3 的表达增加。高剂量（10mg/kg）CsA 处理显著降低细胞色素 C、AIF 和裂解的 caspase-3 的表达，并抑制凋亡途径。SAH 后给予 CsA 可显著改善 EBI，包括皮质凋亡、脑水肿、血脑屏障（BBB）损伤和神经行为缺陷。这些发现表明，早期给予 CsA 可能通过阻断 mPTP 开放和抑制凋亡细胞死亡途径，改善 SAH 模型中的 EBI 并提供神经保护作用。
