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      Melatonin Plays a Protective Role by Regulating miR-26a-5p-NRSF and JAK2-STAT3 Pathway to Improve Autophagy, Inflammation and Oxidative Stress of Cerebral Ischemia-Reperfusion Injury

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          Abstract

          Background

          Melatonin (MT) has potential protective effect on cerebral ischemia-reperfusion injury (CIRI), but its underlying regulatory mechanism has not been identified.

          Purpose

          This study aimed to explore the role of miR-26a-5p-neuron-restrictive silencing factor (NRSF/REST), Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) pathway in the protection mechanism of MT against CIRI in vivo and in vitro.

          Methods

          Sprague Dawley rats were induced with ischemia-reperfusion (IR) in vivo model; PC12 cells were induced with oxygen-glucose deprivation/reperfusion (OGD/R) in vitro model; and MT intervention was conducted before the model was established. The effect of MT on autophagy factors (LC3II/LC3I, P62), inflammatory factors (TNF-α, IL-6, IL-10) and oxidative stress indexes (MDA, GSHPx, SOD) was explored, and then the above three indexes were determined by real-time quantitative PCR, ELISA, and detection kit corresponding to oxidative stress indexes. The neuroprotective effect of MT pretreatment on brain IR injury was evaluated by neurological deficit scores and TUNEL method. The levels of miR-26a-5p and NRSF were detected by real-time quantitative PCR and Western blot, and the interaction between them was evaluated by dual luciferase report. The role of JAK2-STAT3 pathway in MT protection mechanism was verified by pathway blocker (AG490) and Western blot.

          Results

          MT pretreatment can significantly reduce neurological deficit score and neuronal apoptosis, inhibit CIRI autophagy, inflammation and oxidative stress in vivo and in vitro, reduce LC3II/LC3I, TNF-α, IL-6, MDA and increase P62, IL-10, GSHPx, SOD. Further analysis identifies that downregulating miR-26a-5p or upregulating NRSF can eliminate the protective effect of MT, and NRSF is the direct target of miR-26a-5p. The protective effect of MT can also be eliminated under AG490 intervention.

          Conclusion

          MT plays a protective role by regulating miR-26a-5p-NRSF and JAK2-STAT3 pathway to improve CIRI autophagy, inflammation and oxidative stress.

          Most cited references41

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          COVID-19: Melatonin as a potential adjuvant treatment

          This article summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis. The recent outbreak of COVID-19 has become a pandemic with tens of thousands of infected patients. Based on clinical features, pathology, the pathogenesis of acute respiratory disorder induced by either highly homogenous coronaviruses or other pathogens, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response very likely contribute to COVID-19 pathology. This leads to a cytokine storm and subsequent progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and often death. Melatonin, a well-known anti-inflammatory and anti-oxidative molecule, is protective against ALI/ARDS caused by viral and other pathogens. Melatonin is effective in critical care patients by reducing vessel permeability, anxiety, sedation use, and improving sleeping quality, which might also be beneficial for better clinical outcomes for COVID-19 patients. Notably, melatonin has a high safety profile. There is significant data showing that melatonin limits virus-related diseases and would also likely be beneficial in COVID-19 patients. Additional experiments and clinical studies are required to confirm this speculation.
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            Targeting Oxidative Stress and Inflammation to Prevent Ischemia-Reperfusion Injury

            The cerebral ischemia injury can result in neuronal death and/or functional impairment, which leads to further damage and dysfunction after recovery of blood supply. Cerebral ischemia/reperfusion injury (CIRI) often causes irreversible brain damage and neuronal injury and death, which involves many complex pathological processes including oxidative stress, amino acid toxicity, the release of endogenous substances, inflammation and apoptosis. Oxidative stress and inflammation are interactive and play critical roles in ischemia/reperfusion injury in the brain. Oxidative stress is important in the pathological process of ischemic stroke and is critical for the cascade development of ischemic injury. Oxidative stress is caused by reactive oxygen species (ROS) during cerebral ischemia and is more likely to lead to cell death and ultimately brain death after reperfusion. During reperfusion especially, superoxide anion free radicals, hydroxyl free radicals, and nitric oxide (NO) are produced, which can cause lipid peroxidation, inflammation and cell apoptosis. Inflammation alters the balance between pro-inflammatory and anti-inflammatory factors in cerebral ischemic injury. Inflammatory factors can therefore stimulate or exacerbate inflammation and aggravate ischemic injury. Neuroprotective therapies for various stages of the cerebral ischemia cascade response have received widespread attention. At present, neuroprotective drugs mainly include free radical scavengers, anti-inflammatory agents, and anti-apoptotic agents. However, the molecular mechanisms of the interaction between oxidative stress and inflammation, and their interplay with different types of programmed cell death in ischemia/reperfusion injury are unclear. The development of a suitable method for combination therapy has become a hot topic.
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              Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings.

              Melatonin has demonstrated a potential protective effect in central nervous system. Thus, it is interesting to determine whether pre-ischemia melatonin administration could protect against cerebral ischemia/reperfusion (IR)-related injury and the underlying molecular mechanisms. In this study, we revealed that IR injury significantly activated endoplasmic reticulum (ER) stress and autophagy in a middle cerebral artery occlusion mouse model. Pre-ischemia melatonin treatment was able to attenuate IR-induced ER stress and autophagy. In addition, with tandem RFP-GFP-LC3 adeno-associated virus, we demonstrated pre-ischemic melatonin significantly alleviated IR-induced autophagic flux. Furthermore, we showed that IR induced neuronal apoptosis through ER stress related signalings. Moreover, IR-induced autophagy was significantly blocked by ER stress inhibitor (4-PBA), as well as ER-related signaling inhibitors (PERK inhibitor, GSK; IRE1 inhibitor, 3,5-dibromosalicylaldehyde). Finally, we revealed that melatonin significantly alleviated cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency, which were remarkably abolished by tunicamycin (ER stress activator) and rapamycin (autophagy activator), respectively. In summary, our study provides strong evidence that pre-ischemia melatonin administration significantly protects against cerebral IR injury through inhibiting ER stress-dependent autophagy. Our findings shed light on the novel preventive and therapeutic strategy of daily administration of melatonin, especially among the population with high risk of cerebral ischemic stroke.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                06 August 2020
                2020
                : 14
                : 3177-3188
                Affiliations
                [1 ]Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University , Jinzhou, Liaoning, People’s Republic of China
                [2 ]Department of Neurosurgery, The First Affiliated Hospital of Jinzhou Medical University , Jinzhou, Liaoning, People’s Republic of China
                [3 ]Department of Emergency, The First Affiliated Hospital of Jinzhou Medical University , Jinzhou, Liaoning, People’s Republic of China
                [4 ]Department of Gynaecology, The First Affiliated Hospital of Jinzhou Medical University , Jinzhou, Liaoning, People’s Republic of China
                Author notes
                Correspondence: Lin-Lin Wei Department of Gynaecology, The First Affiliated Hospital of Jinzhou Medical University , No. 2, Section 5, Renmin Street, Jinzhou, Liaoning121000, People’s Republic of ChinaTel +86-416-4605293 Email linlinweii@hotmail.com
                Article
                262121
                10.2147/DDDT.S262121
                7418459
                32821085
                e81d0a07-dfb5-4769-b561-c04663fb87b3
                © 2020 Yang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 21 May 2020
                : 28 June 2020
                Page count
                Figures: 8, References: 44, Pages: 12
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                cerebral ischemia-reperfusion injury,melatonin,mir-26a-5p,nrsf,jak2-stat3

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