Focus on the role of mitochondria in NLRP3 inflammasome activation: A prospective target for the treatment of ischemic stroke (Review)

Abstract

Post-ischemic neuroinflammation induced by the innate local immune response is a major pathophysiological feature of cerebral ischemic stroke, which remains the leading cause of mortality and disability worldwide. NLR family pyrin domain containing (NLRP)3 inflammasome crucially mediates post-ischemic inflammatory responses via its priming, activation and interleukin-1β release during hypoxic-ischemic brain damage. Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. In the present review, focus was addressed on the role of mitochondria in cerebral ischemic stroke while keeping NLRP3 inflammasome as a link. Under ischemia and hypoxia, mitochondria are capable of controlling NLRP3 inflammasome-mediated neuroinflammation through mitochondrial released contents, mitochondrial localization and mitochondrial related proteins. Thus, inflammasome and mitochondria may be attractive targets to treat ischemic stroke as well as the several drugs that target the process of mitochondrial function to treat cerebral ischemic stroke. At present, certain drugs have already been studied in clinical trials.

Cardiolipin-Mediated Alleviation of Mitochondrial Dysfunction Is a Neuroprotective Effect of Statin in Animal Model of Ischemic Stroke

“…This results in the opening of the MPTP and the release of cytochrome c from the mitochondria to the cytosol. Previous studies have also described CL, along with ROS, to act as a danger signal for exacerbation of post-stroke cellular damage. ,, In line with earlier results, our study also observed that the post-stroke CL content was significantly upregulated in stroke animals and simvastatin intervention normalized CL levels post-stroke (Figure C). A high CL concentration in the OMM post-stroke might have contributed to the CL-mediated loss of the mitochondrial membrane potential, increased ROS level, and enhanced apoptosis.…”

SDSS ameliorates cerebral ischemia/reperfusion injury by inhibiting CLIC4/NLRP3 inflammasome-mediated endothelial cell pyroptosis

“…Caspase-1 in turn cleaves Pro-IL-1β, Pro-IL-18 and GSDMD-full into active IL-1β, IL-18 and N-terminal domain of GSDMD (GSDMD-N). By inserting into the membrane and forming pores, GSDMD-N causes pyroptosis as well as the release of in ammatory cytokines (IL-1β and IL-18) [30] Accordingly, VX-765, pharmacologic inhibition of Caspase-1, ameliorated ischemia-induced infarction, neurological de cits, and neuronal injury [31]. Further, a signi cant improvement was obtained by inhibiting Caspase-1 in ischemia-associated BBB permeability and integrity via inhibiting pyroptosis [31].…”

Traditional Chinese medicine in treating ischemic stroke by modulating mitochondria: A comprehensive overview of experimental studies

“…The imbalance of mitochondrial fission and fusion after stroke may increase mitochondrial fragmentation, cause aberrant mitochondrial morphology, and disrupt mitochondrial homeostasis, leading to mitochondrial dysfunction and ultimately triggering neuronal death ( Li et al, 2022 ). Additionally, mutation of gene-encoded subunits in mtDNA results in increased ROS generation, which makes mtDNA more susceptible to mutations than nuclear DNA ( Zhang et al, 2022 ). Researchers have reported that the frequency of mtDNA mutations was significantly higher in the brains of patients with ischemic stroke ( Luan et al, 2021 ).…”