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    • Based on these findings the time

    2023-09-18

    Based on these findings, the time point for manipulating autophagy may also determine its role, whereby autophagy induction performed before ischemia could play a protective role but have an opposite effect once ischemia/reperfusion has occurred. This hypothesis is further supported by the protective role of autophagy in ischemic preconditioning and the destruction effect after ischemia/reperfusion (Ravikumar et al., 2010). Ischemic preconditioning treatment significantly reduces permanent focal ischemia-induced PI-3065 mg edema, infarct volume and motor deficits, which is suppressed by the autophagy inhibitors 3-MA and bafliomycin A1 and mimicked by the autophagy inducer rapamycin. These results demonstrate that ischemic preconditioning-induced autophagy activation offers a significant tolerance to the subsequent ischemic insult, and autophagy inducers can achieve the ischemic preconditioning-induced neuroprotective effects (Sheng et al., 2010). In contrast to permanent ischemia, cerebral ischemia-reperfusion is a more complex pathological process and reperfusion-induced brain injury has been considered as a major influence on the outcome of ischemic patients. In fact, reperfusion contributes to neuronal injury by mechanisms distinct from those in ischemia (Aronowski et al., 1997, Hallenbeck and Dutka, 1990). Autophagy induction during brain ischemia may be due to an energy crisis, while the ATP level can be extensively restored by reperfusion (Mengesdorf et al., 2002). Hence, it is likely that mechanisms other than low-energy status are responsible for the retention of autophagy during reperfusion. Blood reperfusion after cerebral ischemia can lead to oxidative stress and ER stress, which are likely to contribute to the induction of autophagy (Zhang et al., 2013). It has been reported that infarcted volumes increases along with duration of ischemia, which can be decelerated by 3-MA. However, suppression of autophagy during reperfusion reinforces ischemia-induced mitochondria-dependent apoptosis (Wen et al., 2008). The aforementioned disparate effects of autophagy in cerebral ischemia and reperfusion solicit the need for revisiting the idea of rescuing the ischemic brain by inhibiting autophagy. Controversies remain concerning the role of the autophagy in human diseases. Even though increasing papers demonstrate an anti-death function of autophagy, some studies suggest the opposite (Ginet et al., 2014). These discrepancies could be due to differences in intervention time, to the limited specificity of pharmacological inhibitors, or to the lack of complete analysis on autophagy processes.
    Autophagy in brain cells The human brain is an organ with high metabolic demands, and brain cells have high energy demand. As a “self-eating” process, autophagy is well established as a starvation-induced process in yeast and mammalian cells and tissues (Yabu et al., 2012). Surprisingly, the regulation of autophagy is organ-dependent in that autophagy enhancement is not detectable in the brain, but observed in the kidney and pancreas, of mice deprived of food for 48h, prompting the hypothesis that the brain nutrients may be compensated from other organs under conditions of starvation (Mizushima et al., 2004). However, in response to pathophysiological conditions, autophagy activation has been observed in the different brain regions and several brain cells. Fundamentally, all brain injury could be broadly defined as homeostatic disorders of brain. As the brain is composed of several cell types, including but not limited to neurons, it is only logical to speculate that all the cell types play a role in health and disease (Verkhratsky et al., 2016). A closer examination of the cell components of the brain, such as neurons, microglia, astrocytes, brain microvascular endothelial cells (BMVECs), pericytes, and vascular smooth muscle cells, may provide a better appreciation of autophagy’s role in the neurological disorders. In this section, we put emphasis on the role of autophagy in neurons, microglia, astrocytes, and BMVECs, which have been well-documented to suffer from and serve essential effects in stroke-induced injuries.