Melatonin Regulates Apoptosis and Autophagy Via ROS-MST1 Pathway in Subarachnoid Hemorrhage.

Feng Liang,Keren Zhou,Jianmin Zhang,Ligen Shi,Jingwei Zheng,Jun Yu,Sheng Chen

doi:10.3389/fnmol.2018.00093

Abstract

Compelling evidence has indicated that imbalance between apoptosis and autophagy may be involved in subarachnoid hemorrhage (SAH). We aimed to investigate the effects and mechanisms of melatonin in the homeostasis of apoptosis and autophagy. One-hundred and forty-eight male Sprague-Dawley rats were intraperitoneally injected with melatonin or vehicle 2 h after SAH induction. Western blotting and an immunofluorescent assay were performed to detect the expression of apoptosis- and autophagy-related proteins. The neuroprotective effect of melatonin attenuating SAH-induced neurological deficit and brain edema may be associated with the suppression of SAH-induced neuronal apoptosis and autophagy. Furthermore, melatonin inhibited the cleavage of mammalian sterile 20-like kinase 1 (MST1) protein by reducing reactive oxygen species (ROS) content. These effects of melatonin on regulating the homeostasis between apoptosis and autophagy could be reversed by an MST1 agonist, chelerythrine, via enhancement of MST1 cleavage. In conclusion, exogenous melatonin alleviates SAH-induced early brain injury (EBI) by suppressing excessive neuronal apoptosis and autophagy. The underlying mechanism may, at least in part, involve the ROS-MST1 pathway.

Highlights

Despite the tremendous progress made in intensive neuroprotective therapy and invasive surgical strategies, aneurysmal subarachnoid hemorrhage (SAH) remains a devastating disorder with a high risk of mortality and severe disability (Laiwalla et al, 2016; van Gijn et al, 2007)
The present study provided the first evidence that melatonin can regulate the homeostasis of apoptosis and autophagy
Melatonin showed neuroprotective effects by alleviating brain edema and improving neurological function. These properties were associated with the suppression of SAH-induced neuronal apoptosis and autophagy

Summary

Introduction

Despite the tremendous progress made in intensive neuroprotective therapy and invasive surgical strategies, aneurysmal subarachnoid hemorrhage (SAH) remains a devastating disorder with a high risk of mortality and severe disability (Laiwalla et al, 2016; van Gijn et al, 2007). Compelling evidence has indicated that an intrinsic apoptotic or autophagic cell death pathway is involved in EBI (Jing et al, 2012; Chen et al, 2014). An appealing hypothesis has been proposed that apoptosis and autophagy may be regulated by a common cellular factor (Dhingra and Kirshenbaum, 2013), no study has explored this missing link between apoptosis and autophagy in EBI after SAH. Melatonin is an evolutionarily conserved neuro-hormone that is predominantly synthesized in and secreted from the pineal gland (Hu et al, 2017). Experimental evidence has demonstrated that both melatonin and its metabolites are potent free-radical scavengers and broadspectrum antioxidants (Zhang et al, 2012), which maintain cellular homeostasis and survival

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