Propofol inhibits parthanatos via ROS–ER–calcium–mitochondria signal pathway in vivo and vitro

Abstract

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.

Impact of general anaesthesia on endoplasmic reticulum stress: propofol vs. isoflurane

“…also reported that the expression of ROS is significantly higher after anaesthesia with isoflurane than after propofol during ischemia-reperfusion injury of the myocardium, although the heart injury scores in that study are similar between the two groups 20. In fact, accumulating evidence has demonstrated that propofol inhibits ROS production 21-23. Therefore, our results are reasonable.…”

Hydrogen: A Novel Option in Human Disease Treatment

“…The accumulation of ROS can trigger the release of calcium from the ER, which results in the depolarization of mitochondria and the loss of the mitochondrial membrane potential [ 26 ]. The negative regulation of ROS and the inhibition of programmed cell death by H 2 help maintain the structure and function of mitochondria.…”

Cell Death Mechanisms Induced by CLytA-DAAO Chimeric Enzyme in Human Tumor Cell Lines

“…Regarding glioblastoma cell lines, the movement of calcium from the ER to the mitochondria, and the consequent lowering of the MMP, is one of the events that usually occurs in the apoptotic process [ 15 ]. Our results with the MMP and calcium mobilization led us to hypothesize that the CLytA-DAAO-induced cell death in pancreatic and colorectal cell lines could be parthanatos, a necrosis-like cell death related to oxidative stress and DNA damage, in which intracellular calcium mobilization associated with a dissipation of the mitochondrial membrane potential occurs [ 13 , 16 ].…”

“…Intracellular calcium is mainly stored in endoplasmic reticulum (ER). Recent studies reported that an uncontrolled ROS increase, such as that produced by the reaction catalyzed by CLytA-DAAO, causes ER stress resulting in calcium release through the inositol-1,4,5-triphosphate receptor (IP3R) and its entrance to the mitochondria [ 13 , 44 , 45 ]. In future studies, the relationship between CLytA-DAAO-induced cell death and ER stress should be addressed.…”

“…In the current study, we tested parthanatos as a possible mechanism involved in the cell death induced by CLytA-DAAO in pancreatic and colorectal carcinoma cell lines. Parthanatos is well-defined as a necrosis-like cell death that occurs when there is excessive DNA damage and has been widely associated with drugs that generate oxidative stress [ 12 , 13 ]. This form of cell death is characterized by the overexpression of Poly (ADP-ribose) polymerase 1 (PARP-1), the cytosolic accumulation of polymeric PAR, the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus, the mobilization of intracellular calcium and the depolarization of the mitochondrial membrane [ 14 ].…”