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    • br Autophagy in hemorrhagic stroke About of all strokes case

    2023-01-13


    Autophagy in hemorrhagic stroke About 87% of all strokes cases are ischemic, the rest being hemorrhagic. ICH and SAH are the two major categories of hemorrhagic strokes (Bruder et al., 2014). Both types of stroke are associated with a high mortality and morbidity rate. The corresponding animal models, including middle cerebral artery occlusion (MCAO) model for ischemic stroke (Li et al., 2014b), autologous blood or collagenase model for ICH (Chen et al., 2015, Rolland et al., 2013), prechiasmatic cistern single-injection model for SAH (Dang et al., 2015), have been set up and widely used in basic and translational medical research. In vitro stroke conditions, such as by OGD/R and oxyhemoglobin treatment, have been introduced to mimic respectively ischemic stroke (Li et al., 2014a) hemorrhagic stroke (Cui et al., 2016), among others. Employing the gold standard for autophagy evaluation, electron microscopy images of Sulfasalazine tissue from SAH rats (Lee et al., 2009), ICH rats (He et al., 2008), and MCAO rats (Xing et al., 2012) have revealed structures consistent with autophagosome/autolysosome properties. Certain marker proteins such as LC3-II have been detected in crude lysates of brain tissue from SAH rats (Lee et al., 2009), ICH rats (He et al., 2008) and MCAO rats (Xing et al., 2012) by immunoblot analysis. Moreover, in vitro evidence also suggests that autophagy could be activated by hypoxia (Li et al., 2014a).
    Discussion and perspectives Comparisons between hemorrhagic and ischemic autophagic response are mainly focused on the endogenous induction of autophagy during stroke, as the involved cell types are common for both hemorrhagic and ischemic stroke. Ischemic stroke causes a sudden block of blood supply to the brain tissue, while blood reperfusion after ischemia leads to oxidative stress and ER stress. During brain ischemia, autophagy induction may be due to energy crisis, while oxidative stress and ER stress are likely to contribute to the induction of autophagy during reperfusion (Zhang et al., 2013). Accumulating evidence suggested that the time point for autophagy induction during ischemic stroke determines its role, whereby autophagy induction performed before ischemia could play a protective role but have an opposite effect once ischemia/reperfusion has occurred (Puyal et al., 2009, Ravikumar et al., 2010, Shi et al., 2012). These results demonstrated that pretreatment-induced autophagy activation could offer a significant tolerance to the subsequent ischemic insult. After ischemia/reperfusion, to resist insufficient nutrients and stress environments, endogenous autophagy was induced (Carloni et al., 2008). In this condition, further induction of autophagy by exogenous inducer may lead to excessive autophagy and aggravate autophagic flux damage, and finally cause nerve injury. Correspondingly, during hemorrhagic stroke, clot components or productions, such as hemoglobin, ferrous citrate and thrombin, have been shown to participate in endogenous autophagy regulation. For example, a detrimental role of iron and ferrous citrate-induced autophagy and a beneficial role of thrombin-induced autophagy in ICH have been reported (Chen et al., 2012, Hu et al., 2011, Wang et al., 2015). However, as the disproportionate distribution of the studies on the 2 types of stroke, knowledge on the key differences between ischemic vs hemorrhagic autophagic response is still incomplete. Mechanisms that govern cell specificity of autophagy in stroke remain incompletely answered. For example, unique features of neuronal autophagy are mainly drawn from the special synaptic structure of the neurons. The strict location of lysosomes at the juxtanuclear cytoplasm and the formation of autophagosomes at dendrites and synaptic terminal regions suggests that autophagosomes formed in dendrites and synaptic terminal regions must be transported to the lysosome in the cell body to finish an intact autophagic flux. And, a previous kinetic analysis of organelle movements further indicated that the retrograde axonal transport of autophagosomes is strictly necessary for its fusion with lysosomes in cultured neurons (Hollenbeck, 1993). As a prenylated SNARE, ykt6 is selectively expressed in brain neurons and locates at dendrites and synaptic terminal regions revealed by immunofluorescence microscopy (Hasegawa et al., 2003). And, ykt6 appears to be specialized for the trafficking of a unique membrane compartment, perhaps related to lysosomes, involved in aspects of neuronal function (Hasegawa et al., 2003). The special synaptic structure of the neurons and the selective expression of ykt6 in neurons may suggest a possibility for selective regulation of autophagy in neurons for stroke treatment.