Pharmacological Modulation of Autophagy for Neuroprotection in Ischaemic Stroke

Abstract

Autophagy is a highly regulated, catabolic process, through which macromolecules such as damaged organelles and proteins are degraded and recycled to maintain cellular homeostasis. Various studies have shown the role of autophagy activation in the brain cells such as astrocytes, microglia, neurons and capillary endothelial cells upon an ischaemic insult. The underlying mechanism and the role of autophagy in ischaemic stroke, however, are yet to be fully elucidated. Recent studies have suggested that insufficient or excessive autophagy results in nerve damage and cell death whereas mild/moderate autophagy has a neuroprotective effect. It has been proposed that autophagy may be a therapeutic target in stroke treatment; however, there is a lot of debate as to whether induction or diminution of autophagy plays a role in neuronal survival after cerebral ischaemia and indicate that it has a dual role depending on the time of induction of autophagy. This review has summarized the role of autophagy in ischaemic stroke and explored effects of pharmacological autophagy modulators in ischaemic stroke treatment. Further studies are needed for translating the potential therapeutic approach in stroke treatment aiming at characterizing the timing, amount and specificity of the autophagy modulation.Recently, studies have found autophagy to be a key regulatory factor in ischemic stroke, unveiling a new range of potential therapeutic targets for neuroprotection (Papadakis et al., 2013). Nevertheless, the full mechanism has not yet been construed, hence, there is still controversy over whether autophagy is neuroprotective or pro-death under hypoxia (Wang et al., 2018a). The aim of this review article is to elucidate the role of autophagy in ischaemic stroke and explore pharmacological modulation of autophagy as therapeutic use for neuroprotection in ischaemic stroke.

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce autophagy and have a protective effect in an in-vitro ischaemia model

“…MTT assay assesses mitochondrial catabolism and cell metabolic activity, which can be reduced in cells whilst retaining cell membrane integrity represented by LDH assay 28 . www.nature.com/scientificreports www.nature.com/scientificreports/ Next, the role of the PHD inhibitors on three major autophagic marker, LC3, p62 and Beclin1 was studied using rapamycin as a positive control inducer of autophagy 29 . Beclin1 plays an important role in induction of autophagy.…”

“…Autophagy is a self-catabolic process of damaged or dysfunctional cellular components, which are recycled for providing energy and nutrients 29 . A number of studies demonstrate that mild/moderate autophagy has a neuroprotective effect on ischaemic stroke whereas insufficient or excessive autophagy results in nerve damage and cell death 22,29 . A study by Park et al 38 showed ischaemic preconditioning (IPC) increased generation of autophagosomes and lysosomal activity.…”

Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy

“…Jin et al [112] reported increased angiogenesis and neurogenesis and improved functional recovery following metformin treatment post tMCAo. Since AMPK coordinates control of cell growth and autophagy [113], the neuroprotective effects could be due to autophagy induced by metformin [114]. Furthermore, metformin has also been shown to inhibit NF-κB cascade and suppress neuroinflammation [115,116].…”

The Use of Neuroprotective Agents in Treating Geographic Atrophy

“…Rapamycin, a drug that induces autophagy, has been shown to confer neuroprotection in fly and mouse models of Huntington’s disease [114]. However, if autophagic recycling becomes imbalanced, it can lead to neuronal cell death; thus, careful control of autophagy is vital [112, 115]. At present, it is not clear what specific modulation of autophagy is required for neuroprotection [115]; control of autophagy could be a promising future strategy, but further studies are required to establish its role and potential for therapeutic use.…”