The Department of Anesthesia, Affiliated hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Cell Death Dis. 2018 Sep 17;9(10):932. doi: 10.1038/s41419-018-0996-9.
Parthanatos is a new form of programmed cell death. It has been recognized to be critical in cerebral ischemia-reperfusion injury, and reactive oxygen species (ROS) can induce parthanatos. Recent studies found that propofol, a widely used intravenous anesthetic agent, has an inhibitory effect on ROS and has neuroprotective in many neurological diseases. However, the functional roles and mechanisms of propofol in parthanatos remain unclear. Here, we discovered that the ROS-ER-calcium-mitochondria signal pathway mediated parthanatos and the significance of propofol in parthanatos. Next, we found that ROS overproduction would cause endoplasmic reticulum (ER) calcium release, leading to mitochondria depolarization with the loss of mitochondrial membrane potential. Mitochondria depolarization caused mitochondria to release more ROS, which, in turn, contributed to parthanatos. Also, we found that propofol inhibited parthanatos through impeding ROS overproduction, calcium release from ER, and mitochondrial depolarization in parthanatos. Importantly, our results indicated that propofol protected cerebral ischemia-reperfusion via parthanatos suppression, amelioration of mitochondria, and ER swelling. Our findings provide new insights into the mechanisms of how ER and mitochondria contribute to parthanatos. Furthermore, our studies elucidated that propofol has a vital role in parthanatos prevention in vivo and in vitro, and propofol can be a promising therapeutic approach for nerve injury patients.
细胞发生程序性死亡是一种新的形式。现已证实其在脑缺血再灌注损伤中起关键作用，活性氧（ROS）可诱导细胞发生程序性死亡。最近的研究发现，丙泊酚是一种广泛应用的静脉麻醉剂，它对 ROS 具有抑制作用，并在许多神经疾病中具有神经保护作用。然而，丙泊酚在细胞发生程序性死亡中的功能作用和机制尚不清楚。在这里，我们发现 ROS-内质网-钙-线粒体信号通路介导了细胞发生程序性死亡，以及丙泊酚在细胞发生程序性死亡中的意义。接下来，我们发现 ROS 的过度产生会导致内质网（ER）钙释放，导致线粒体去极化和线粒体膜电位丧失。线粒体去极化导致线粒体释放更多的 ROS，进而导致细胞发生程序性死亡。此外，我们发现丙泊酚通过抑制 ROS 的过度产生、内质网钙释放和线粒体去极化来抑制细胞发生程序性死亡。重要的是，我们的结果表明，丙泊酚通过抑制细胞发生程序性死亡、改善线粒体和内质网肿胀来保护脑缺血再灌注。我们的发现为 ER 和线粒体如何参与细胞发生程序性死亡提供了新的见解。此外，我们的研究表明，丙泊酚在体内和体外预防细胞发生程序性死亡中具有重要作用，丙泊酚可能是神经损伤患者的一种有前途的治疗方法。
