Lots of words but NO ACTIONABLE INTERVENTIONS! So useless; you're fired!
Ginsenoside Rg1 ameliorates cerebral ischemia-reperfusion injury by regulating Pink1/ Parkin-mediated mitochondrial autophagy and inhibiting microglia NLRP3 activation
Keywords
1. Introduction
Cerebral ischemia-reperfusion injury (CI/RI) refers to cerebral ischemia that triggers cellular dysfunction and cell death after a specific period, and ischemic tissues are rescued by restoration of blood flow and perfusion. However, reperfusion itself causes tissue damage, which in turn aggravates the degree of cerebral tissue damage (Lim et al., 2021). The complex pathogenesis of CIRI involves multiple components. The early decline in cerebral blood flow causes energy loss and impairs energy synthesis, leading to depolarization of neuronal cell membranes and imbalance of intra- and extracellular ion homeostasis. This can lead to a series of cascade reactions after cerebral ischemia inducing mitochondrial damage, oxidative stress, inflammatory response, Ca2+ overload, accelerating neuronal apoptosis, and thus hindering the recovery of neurological function (Zhang et al., 2022). In recent years, research on treating cerebral ischemia-reperfusion injury by regulating mitochondrial autophagy-related molecules has made some progress, which is of positive significance for protecting neurons from ischemia-reperfusion injury and improving patient healing.
As one of the organism's most critical and sensitive organelles, mitochondria plays a crucial role in cell survival (Koch et al., 2017). Among the multiple pathogenesis of cerebral ischemia-reperfusion injury, the mechanism of mitochondrial autophagy plays an important role. Moderate enhancement of mitochondrial autophagy attenuates cerebral ischemia/reperfusion injury, whereas dysfunctional mitochondrial autophagy activates various pathological mechanisms to exacerbate cellular damage (Wu et al., 2021). The Pink1/Parkin pathway is a classical pathway mediating mitochondrial autophagy. Pink1 (PTEN-induced kinase1) senses mitochondrial damage and activates Parkin through phosphorylation and ubiquitination. Activated Parkin constructs a ubiquitin chain on damaged mitochondria and labels them as mitochondria with ubiquitin. Activated Parkin builds ubiquitin chains on damaged mitochondria, tagging them for degradation of damaged mitochondria (Eiyama and Okamoto, 2015, Bingol and Sheng, 2016). Damaged mitochondria releases large amounts of reactive oxygen species, which are involved in the activation of NLRP3 (NLR Family Pyrin Domain Containing 3) inflammatory vesicles, the activation of which further triggers apoptosis and tissue damage. Studies have shown that inhibiting mitochondrial reactive oxygen species production can suppress NLRP3 inflammasome activation (Lin et al., 2019).
Ginsenoside Rg1 (Rg1) is the main active ingredient of ginseng, which can produce significant neuroprotective effects against cerebral ischemic injury through the interaction of different signaling pathways (Xie et al., 2018). Studies have shown that Rg1 can improve ischemic conditions by repairing inflammation associated with dendrites, axons, microglia, and astrocytes, which can significantly reduce apoptosis (Yang et al., 2023, Han et al., 2022a). However, little is known about the mechanism of action of Rg1 in regulating mitochondrial function to inhibit microglia NLRP3 activation to ameliorate cerebral ischemia-reperfusion injury. We utilized aspirin as a positive drug to eliminate the interference of negative results, and set up the FCCP group as a PINK1 activator, and set up the Rg1+CsA group to test whether Rg1 could reverse mitochondrial autophagy caused by CsA. In this study, we observed the changes in mitochondrial morphology and structure as well as the effects on the expression levels of mitochondrial autophagy-related proteins before and after administration of Rg1 in rats with cerebral ischemia-reperfusion model. The possible mechanism of action of Rg1 for the treatment of cerebral ischemia-reperfusion injury was further elucidated by in vivo and in vitro experiments. This will further promote the development of drug candidates to improve cerebral ischemia-reperfusion injury and provide more information and data support for clinical application.
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