Melatonin Treatment Regulates SIRT3 Expression in Early Brain Injury (EBI) Due to Reactive Oxygen Species (ROS) in a Mouse Model of Subarachnoid Hemorrhage (SAH)

Abstract

BackgroundA mouse model of subarachnoid hemorrhage (SAH) investigated the effects of melatonin treatment on the generation of reactive oxygen species (ROS) and the activation of the SIRT3 gene in early brain injury (EBI).Material/MethodsMale C57BL/6J mice were assigned to three groups: the SAH group; the sham group; and the SAH + melatonin-treated group (intraperitoneal dose, 150 mg/kg). TUNEL was used to study apoptosis of neuronal cells, Western-blot and immunohistochemistry detected expression of Sirt3, Bcl-2, superoxide dismutase 2 (SOD2), Bax, and cleaved caspase-3. Real-time polymerase chain reaction (PCR) and a luciferase reporter assay evaluated the effects of melatonin on SIRT3 gene expression. Malondialdehyde (MDA) and the reactive oxygen species (ROS) scavenger, reduced glutathione (GSH), and its ratio with oxidized glutathione (GSSG) was measured.ResultsThe increase in neurological score and increase in cerebral edema following SAH were reduced in the SAH + melatonin-treated group. Neuronal apoptosis following SAH was reduced in the SAH + melatonin-treated group. Increased levels of SOD2, Bax, and cleaved caspase-3 following SAH were reduced in the SAH + melatonin-treated group; reduced levels of Sirt3 and Bcl-2 following SAH were increased in the SAH + melatonin-treated group. The GSH: GSSG ratio was increased, and the MDA level was decreased when melatonin treatment was used following SAH. Melatonin upregulated SIRT3 expression by increasing the transcription efficiency of the SIRT3 promoter in human glioma cell lines U87 and U251.ConclusionsMelatonin provided protection from the effects of EBI following SAH by regulating the expression of murine SIRT3.

Melatonin pretreatment alleviates renal ischemia‐reperfusion injury by promoting autophagic flux via TLR4/MyD88/MEK/ERK/mTORC1 signaling

“…Melatonin is reported to exert both direct free radical scavenging and antioxidative effects, thereby preventing the production of ROS that damage cell membranes. 26 Consistent with the above observations, the protective effect of melatonin was further proved by reduced oxidative stress as manifested by decreased lipid peroxidation (less generation of MDA and larger GSH/GSSG ratio) and increased antioxidant capacity (higher SOD and catalase activities). We further demonstrated that melatonin pretreatment significantly limited pro-inflammatory cytokine production and neutrophil and macrophage infiltration, all of which are evoked by IR injury and considered major mediator of acute kidney injury.…”

Role and mechanism of ROS scavengers in alleviating NLRP3‐mediated inflammation

“…The work demonstrated that melatonin upregulated mitophagy‐associated proteins and reduced ROS generation, thus inhibiting NLRP3 inflammasome activation. In a report this year, SIRT3 protein expression enhanced by melatonin was observed to reduce ROS, then inhibit NLRP3 inflammasome activation and protect neuronal cells . SIRT3 protein locates at mitochondria and is associated with mitophagy , which may be one main target of melatonin regulating ROS‐NLRP3 inflammasome pathway, as illustrated in Fig.…”

“…Many of them clear ROS through enhancing antioxidase expression via Nrf2 pathway, thus regulating ROS‐mediated NLRP3 inflammasome expression and/or activation. Autophagy, including mitophagy, may also mediate ROS reduction and suppress NLRP3 inflammatory signaling pathway . Activation of autophagy and decreased ROS production was observed when quercetin suppressed NLRP3 inflammasome activation in epithelial cells infected with E. coli O157:H7 .…”

“…Illustrated mechanism of melatonin attenuating early brain injury (EBI) involved with ROS. Melatonin could directly scavenge ROS, and it can also enhance SIRT3 protein expression at mitochondria membrane to reduce mtROS production . In addition, melatonin is also able to activate antioxidases through Nrf2 pathway .…”

Will Sirtuins Be Promising Therapeutic Targets for TBI and Associated Neurodegenerative Diseases?

“…Melatonin is a powerful antioxidant that attenuates early brain injury-induced oxidative stress and neuronal apoptosis by activating the SIRT1/NF-kB pathway (Zhao et al, 2017). Furthermore, melatonin upregulates the expression of SIRT3 to reduce the production of ROS and resist oxidative stress (Yang et al, 2018). Estrogen also regulates SIRT1.…”