A Double‐Edged Sword with Therapeutic Potential: An Updated Role of Autophagy in Ischemic Cerebral Injury

Abstract

SUMMARYCerebral ischemia is a severe outcome that could cause cognitive and motor dysfunction, neurodegenerative diseases and even acute death. Although the existence of autophagy in cerebral ischemia is undisputable, the consensus has not yet been reached regarding the exact functions and influence of autophagy in cerebral ischemia. Whether the activation of autophagy is beneficial or harmful in cerebral ischemia injury largely depends on the balance between the burden of intracellular substrate targeted for autophagy and the capacity of the cellular autophagic machinery. Furthermore, the mechanisms underlying the autophagy in cerebral ischemia are far from clear yet. This brief review focuses on not only the current understanding of biological effects of autophagy, but also the therapeutic potentials of autophagy in ischemic stroke. There are disputes over the exact role of autophagy in cerebral ischemia. Application of chemical autophagy inhibitor (e.g., 3-methyladenine) or inducer (e.g., rapamycin) in vitro and in vivo was reported to protect or harm neuronal cell. Knockdown of autophagic protein, such as Beclin 1, was also reported to modulate the cerebral ischemia-induced injury. Moreover, autophagy inhibitor abolished the neuroprotection of ischemic preconditioning, implying a neuroprotective effect of autophagy. To clarify these issues on autophagy in cerebral ischemia, future investigations are warranted.

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

“…Autophagy may play a pro‐death or a pro‐survival role of cells 4. A large amount of research have shown that autophagy is a double‐edged sword involved in health and disease 5. Whether autophagy protects or aggravates the renal damage in cisplatin‐induced AKI is unclear.…”

Involvement of autophagy in hypoxic-excitotoxic neuronal death

“…However, in other situations, autophagy can be deleterious and contribute to cell death either by triggering apoptosis or necrosis or as an independent cell death mechanism ("autophagic cell death" or type II programmed cell death). 2,3 In neurons the question of whether enhanced autophagy promotes cell death or cell survival is a subject of considerable debate [3][4][5][6][7][8] especially in excitotoxic conditions such as cerebral ischemia. Some studies have suggested a protective role of neuronal autophagy in cerebral hypoxia/ ischemia, 9,10 whereas others have demonstrated a death-mediating role.…”

Ischemic Stroke Mechanisms, Prevention, and Treatment: The Anesthesiologist’s Perspective

“…Autophagy is a well-known player in cellular homeostasis. Superfluous or damaged proteins and organelles are packed into autophagosomes, which drain into lysosomes for degradation (58,59,70,71). The role of autophagy in cell death, particularly in ischemic cell death, is controversial and under intense study.…”

“…The effects of autophagy are likely context dependent. Numerous studies have demonstrated that autophagy is activated following ischemic insult (59,(62)(63)(64)(71)(72)(73). Whether autophagy is a driver of cell death in ischemia is still not clarified.…”

“…Whether autophagy is a driver of cell death in ischemia is still not clarified. Some experimental evidence suggests that reducing autophagy early after infarction can attenuate injury progression (71,(74)(75)(76). Conversely, other studies indicate that promoting autophagy may induce cells to undergo apoptotic rather than necrotic cell death, leading to reduced lesion sizes (71,77,78).…”