Defining the multiple roles of autophagy in stroke has been
Defining the multiple roles of autophagy in stroke has been a rapidly evolving and exciting venue for translational research, with innovative products being applied from bench to bedside. Spanning pharmacological pathway manipulation and functional experimental validation, altered autophagy activation following stroke contributes to a group of divergent phenotypes. First, a careful examination of the bulk of studies suggests that excitotoxic conditions following ischemic stroke and clot components or products following hemorrhagic stroke can affect the role of autophagy in stroke largely influenced by the individual’s presenting condition, while the selectivity of autophagy substrate and the integrity of autophagic flux appear relegated at the molecular levels. An MK-2206 of these factors may explain the observed dual role of autophagy in stroke. Second, the role of autophagy displays cell specificity in brain. Some of the controversies on the results, especially the in vitro experiments, may come from the variety of models utilized, for example, in some studies only one cell type is examined. Third, since stroke-induced autophagy itself has both beneficial and detrimental roles at part in a time-dependent manner, recognizing the optimal time point for initiating interventions in targeting autophagy should be considered. Furthermore, identifying the mitigating factors that mediate the inappropriate activation of autophagy pathway in animals with stroke warrants investigations. Fourth, due to the extensive roles of autophagy in many cellular functions, inhibition of the entire autophagy or inadaptable activation of autophagy may not be ideal. Fifth, further understanding of the crosstalk between autophagy and apoptosis, and between autophagy and inflammation will facilitate the identification of the effective biological pathways to normalize autophagy and prevent brain injury in stroke. Finally and of utmost consideration, the desire to translate autophagy-based treatments for stroke to the clinic should be accompanied by robust preclinical studies of autophagy in cell culture and animal disease models. The critical concern is whether these predictions from animal models could be translated into potential clinical insights regarding the roles of autophagy in human disease. At the very least, if our lessons of a highly regulated and selective autophagy from animal experiments are correct, the next preclinical challenge is to find specific strategies that can maintain the balance between induction of autophagy and regulation of intact autophagic flux, while circumventing detrimental effects associated with inhibition of autophagy. To realize this goal, a concerted effort should coalescing the multiple lines of investigations, including the signaling control of autophagy, the regulation of autophagosome/lysosome fusion, and the mechanistic basis for disease- and cell-related specificity in autophagy regulation. In conclusion, both basal and stress-induced autophagy likely plays an important role in promoting mammalian health. Targeting autophagy for stroke treatment is an exciting area of research with many unanswered questions that should be carefully and critically addressed by future investigations in order to translate such therapy from the laboratory to the clinic.