br Introduction Stroke is a devastating

Introduction Stroke is a devastating condition that causes cognitive and motor dysfunction, neurodegenerative diseases and even acute death, and is a leading cause of mortality and morbidity worldwide (Chen et al., 2014a, Wang et al., 2016). Thus, exploration or identification of novel therapeutic targets becomes a major task and challenge in the field. Stroke is the third leading cause of death and disability worldwide. There are two main types of stroke: ischemic strokes resulting from lack of blood supply to the brain, and hemorrhagic strokes due to an abnormal vascular structure or the rupture of a blood vessel. As an intracellular degradation system, autophagy is generally thought to be neuroprotective because it helps to clear aggregated-protein and damaged organelles associated with several stress environments, such as neurodegeneration (Rubinsztein et al., 2015). Given that autophagy can promptly respond to energy supply and insufficient nutrients, it is not surprising that it is extensively observed in ischemic Tankyrase Inhibitors 22 tissues (Zhang et al., 2013), and in tandem several lines of evidence also indicate the existence of autophagy in hemorrhagic stroke (Yang et al., 2014, Chang et al., 2014). However, the exact influence and function of autophagy in stroke have not yet reached a consensus. These controversies have brought attention to characterizing the elaborate regulatory mechanisms of autophagy in stroke. Thus, this review focuses on not only elucidating the current understanding of biological effects of autophagy, but also in probing the molecular mechanisms underlying the role of autophagy, and its therapeutic potential in stroke. We commence this review article by describing the basic process of autophagy and methods for assessing autophagy. We will then outline the crosstalk between apoptosis, necrosis, and autophagy, and the possible mechanisms associated with autophagy in sequestration of inflammation in stroke. We emphasize the topic on the dual role of autophagy in neurovascular diseases by delving into complex pathological consequences of stroke, including inflammation and cell death regulation. Finally, we discuss the clinical challenges in the future development of therapeutic strategies designed to target the autophagic pathways in stroke. As the role of autophagy in ischemic stroke has been reviewed in detail (Chen et al., 2014d, Wei et al., 2012), we gave special attention to hemorrhagic stroke in this paper.
Autophagy There are three different pathways of autophagy that are commonly described, namely chaperone-mediated autophagy, microautophagy, and macroautophagy (Parzych and Klionsky, 2014). Chaperone-mediated autophagy, or CMA, involves the recognition of substrate proteins containing the recognition site for the heat shock cognate protein70 (hsc70) complex, a pentapeptide KFERQ, which allows substrate proteins to bind to the chaperone and to form the substrate/chaperone complex. Upon recognition, with the assistance of the lysosomal hsc70 chaperone, substrate proteins translocate across the lysosome membrane, whereupon they become degraded. Accordingly, CMA is extremely selective in facilitating specific substrates to cross the lysosomal barrier (Huber and Teis, 2016, Tasset and Cuervo, 2016). Microautophagy, which has been mainly researched in yeast (Li et al., 2012), involves the direct sequestration of cytoplasmic material by lysosomes. Most importantly, much of the pioneering work has focused on macroautophagy, which is one of the major routes for recycling and orderly degradation of cellular constituents. During this process, targeted cytoplasmic components are isolated and engulfed within a double-membraned vesicle called an autophagosome. Thereafter, the autophagosome fuses with a lysosome to form an autolysosome and the contents are degraded and recycled (Ariosa and Klionsky, 2016). Macroautophagy, initially studied in yeast, has been suggested to afford a protective effect against cellular starvation, which is conserved across evolution (Zhang et al., 2013). In addition, as the most studied form of autophagy, increasing studies in mammalian systems demonstrate the involvement of macroautophagy (hereafter referred to as “autophagy”) in diverse areas of physiology and disease, such as cancer (Chen et al., 2014c), aging (Kroemer, 2015), immunity (Zhou and Zhang, 2012), atherosclerosis (De Meyer et al., 2015), neurodegenerative disorders (Vidal et al., 2014), and cerebrovascular disease, including ischemic stroke (Huang et al., 2015), intracerebral hemorrhage (ICH) (Chang et al., 2014), and subarachnoid hemorrhage (SAH) (Chen et al., 2015).