Abstract
According to the recent findings, autophagy modulation is being a potential therapeutic target in the management of ischemic stroke in a pre-clinical setting. However, the pros and cons of autophagic response strongly depend on the activation time of autophagy after injury. In this systematic review, we aimed to explore the impacts of pharmacological modulation of autophagy on infarct size in experimental ischemic stroke models. Based on our preliminary search, 3551 publications were identified. Of twenty-nine publications that met the inclusion criteria, twenty studies reported infarct volume reduction by percentage (%) with no evidence of any publication bias while nine studies reported by mm3, which had publication bias (39.25 units, standardized mean differences (SMD) = 41.92, 95% confidence interval (CI): 30.33 to 53.51). Based on a meta-analysis, the point estimate (pooled mean difference) for improvement of infarct volume during autophagy modulation according to the mm3 and percentage were 35.64 (mean differences (MD) = 35.64, 95% CI: 26.43 to 44.85, z-value = 7.58, p-value < 0.001) and 14.38 (MD = 14.38, 95% CI = 10.50 to 18.26, z-value = 7.26, p < 0.001) units, respectively. Despite the undeniable role of autophagy in ischemic stroke, the dichotomous effects of autophagy regarding infarct volume reduction should be taken into account. Based on our findings, the studies included in this meta-analysis mostly reported a negative relation between autophagy induction and stroke volume development due to over-activity of autophagy upon the severe ischemic stroke; therefore, further pre-clinical studies are also recommended to establish adjusted autophagy with considering a time-dependent effect as a promising therapeutic target.
Highlights
Ischemic stroke (IS), one of the devastating disorders, is the intended second leading cause of mortality and disability followed by vascular occlusion and irreversible damage of the brain tissue [1, 2]
A catabolic-conserved process through the breakdown and subsequent recycling of cellular constituents, is an essential physiological intracellular process for maintaining cellular homeostasis and simultaneously participates in bio-energetic procedures under various stress conditions [8]. This phenomenon is highly regulated by numerous molecules such as microtubule-associated protein 1A light chain 3 (LC3), Beclin-1, and P62 that have a necessary role in the regulation of the autophagy signaling pathway [9]
According to the obtained data from the included articles, the animals were assigned to the control group without any intervention, the stroke group induced by permanent/transient MAOC manner, and treatment groups received autophagy modulators
Summary
Ischemic stroke (IS), one of the devastating disorders, is the intended second leading cause of mortality and disability followed by vascular occlusion and irreversible damage of the brain tissue [1, 2]. A catabolic-conserved process through the breakdown and subsequent recycling of cellular constituents, is an essential physiological intracellular process for maintaining cellular homeostasis and simultaneously participates in bio-energetic procedures under various stress conditions [8]. This phenomenon is highly regulated by numerous molecules such as microtubule-associated protein 1A light chain 3 (LC3), Beclin-1, and P62 (a scaffold protein) that have a necessary role in the regulation of the autophagy signaling pathway [9]. The excessive activation of autophagy and related effectors in neural cells have been firmly established in a variety of focal ischemic stroke models such as experimental middle cerebral artery occlusion (MCAO). The main purpose of this systematic review refers to uncover a total pattern of infarct volume evolution after autophagy modulation quantitatively via meta-analysis in the experimental models of stroke
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