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  • br Autophagy and cell death pathways in ischemic

    2024-05-15


    Autophagy and cell death pathways in ischemic stroke Although very important for the effects on post-ischemic dihydrofolate reductase inhibitor antibacterial injury, autophagy is not the only mechanism of action involved in cell death. Necrosis and apoptosis are two other distinct forms of cell death with great difference in morphology and mechanism. Conventionally, necrosis is an uncontrolled fatal event resulting from loss of homeostasis and characterized by swelling and disruption of the cytoplasmic membrane. Recently, the discovery of necro-apoptosis, which is also called as “necroptosis”, showed that cells undergo necrosis in a programmed fashion (Vandenabeele et al., 2010). Apoptosis is believed to be a programmed cell death characterized by a distinct set of morphological and biochemical changes, including apoptotic body formation, membrane blebbing, mitochondrial membrane potential loss, cell shrinkage, nuclear condensation and chromosomal DNA fragmentation (Nikoletopoulou et al., 2013). While necroptosis and apoptosis are mechanistically and morphologically distinct processes, there is a significant cross-talk between them in ischemic stroke. Furthermore, autophagy shares common molecular mediators with necroptosis and apoptosis, such as AMPK, Bcl-2 and p62 (Levine et al., 2015). These critical integrative hubs also regulate cell metabolic status sensing, protein complex formation and membrane trafficking during the autophagy, necroptosis and apoptosis processes by controlling signaling transduction (Fig. 4).
    Interplay between autophagy and other cellular processes in ischemic stroke
    Conclusions and perspectives It is clear that autophagy plays a role in regulating brain homeostasis in ischemic stroke by controlling neural survival and death via numerous regulatory factors (Fig. 7). There is a growing interest in studying the role and regulation of the autophagy pathway in ischemic stroke partly because of the notion that autophagy is adaptive cytoprotection against stresses; however, the research community has yet to reach a consensus on the exact action of autophagy in stroke. We proposed previously that the activation of autophagy pathway in brain upon ischemic stimuli may be a double-edged sword for neural survival after ischemic stroke (Wei et al., 2012). However, the complexity and heterogeneity of experimental settings, including the differences in the animal species/ages, cell/animal model, the intensity of ischemia and time-duration of brain ischemia may contribute to the discrepancy in the experimental outcome. For example, the well-regulated autophagy can function as a rapid response to overcome various stress to increase cell viability, while the prolonged and excessive autophagy by ischemia is fatal. In fact, multiple lines of evidence including ours have demonstrated that autophagy is neuroprotective in the early stage of brain ischemia and becomes neurotoxic when ischemia lasts longer (Wang et al., 2012). Moreover, a theory of bidirectional action for autophagy was previously proposed: autophagy may be protective during ischemia, whereas it may be detrimental dihydrofolate reductase inhibitor antibacterial during reperfusion (Matsui et al., 2007). Therefore, it is likely that the exact role of autophagy in ischemic stroke depends on the status of blood flow reperfusion into brain during ischemic insult. In addition, several pharmacological agents, such as 3-MA and rapamycin, are used widely to evaluate the effect of autophagy inhibition on ischemic neural injury. Due to the relative low specificity of the pharmacological agents, which affect cell growth and secretion, the conclusions based on those studies are tentative. It should be noted that, the application of genetic tools, such as gene knockout of autophagy genes, has also limitation because many autophagic genes also regulate autophagy-unrelated biological functions (Subramani and Malhotra, 2013). Thus, multiple approaches including pharmacological and genetic manipulation should be considered together in order to draw a valid conclusion.