Melatonin attenuates reactive astrogliosis and glial scar formation following cerebral ischemia and reperfusion injury mediated by GSK‐3β and RIP1K

Abstract

Even though astrocytes have been widely reported to support several brain functions, studies have emerged that they exert deleterious effects on the brain after ischemia and reperfusion (I/R) injury. The present study investigated the neuroprotective effects of melatonin on the processes of reactive astrogliosis and glial scar formation, as well as axonal regeneration after transient middle cerebral artery occlusion. Male Wistar rats were randomly divided into four groups: sham‐operated, I/R, I/R treated with melatonin, and I/R treated with edaravone. All drugs were administered via intraperitoneal injection at the onset of reperfusion and were continued until the rats were sacrificed on Day 7 or 14 after the surgery. Melatonin presented long‐term benefits on cerebral damage after I/R injury, as demonstrated by a decreased infarct volume, histopathological changes, and reduced neuronal cell death. We also found that melatonin attenuated reactive astrogliosis and glial scar formation and, consequently, enhanced axonal regeneration and promoted neurobehavioral recovery. Furthermore, glycogen synthase kinase‐3 beta (GSK‐3β) and receptor‐interacting serine/threonine‐protein 1 kinase (RIP1K), which had previously been revealed as proteins involved in astrocyte responses, were significantly reduced after melatonin administration. Taken together, melatonin effectively counteracted the deleterious effects due to astrocyte responses and improved axonal regeneration to promote functional recovery during the chronic phase of cerebral I/R injury by inhibiting GSK‐3β and RIP1K activities.

MiR‐199a‐5p enhances neuronal differentiation of neural stem cells and promotes neurogenesis by targeting Cav‐1 after cerebral ischemia

“…Under pathophysiological conditions, most NSCs eventually differentiate into astrocytes which in the injured brain can be transformed into reactive astrocytes and promote the formation of glial scars, thereby inhibiting axon regeneration and hindering neurogenesis 13,37 . In this study, we found that the expression of miR‐199a‐5p elevated at 14th d after cerebral ischemia.…”

Systematic review of melatonin in cerebral ischemia-reperfusion injury: critical role and therapeutic opportunities

“…Chen et al reported that administration with melatonin attenuated TRIF expression, an adapter molecule of TLRs, and ultimately prevented the conversion of astrocytes from anti-inflammatory (A2) to pro-inflammatory (A1) phenotype ( Chen et al, 2020 ). In addition, in rats subjected to MCAO/R, melatonin administration could effectively decrease glial fibrillary acid protein (GFAP) expression, C3, and S100A10, suggesting that melatonin inhibited reactive astrogliosis and A1 astrocyte polarization ( Yawoot et al, 2022 ). Besides, melatonin was also shown to reduce astrocyte-mediated inflammatory response by inhibiting glycogen synthase kinase-3 beta (GSK-3β) expression levels and receptor-interacting serine/threonine-protein 1 kinase (RIP1K) activities, consequently enhanced axonal regeneration and promoted neurobehavioral recovery ( Yawoot et al, 2022 ).…”

“…In addition, in rats subjected to MCAO/R, melatonin administration could effectively decrease glial fibrillary acid protein (GFAP) expression, C3, and S100A10, suggesting that melatonin inhibited reactive astrogliosis and A1 astrocyte polarization ( Yawoot et al, 2022 ). Besides, melatonin was also shown to reduce astrocyte-mediated inflammatory response by inhibiting glycogen synthase kinase-3 beta (GSK-3β) expression levels and receptor-interacting serine/threonine-protein 1 kinase (RIP1K) activities, consequently enhanced axonal regeneration and promoted neurobehavioral recovery ( Yawoot et al, 2022 ). Mechanistically, suppression of GSK-3β can reduce NF-κB nuclear translocation and upregulate cyclic AMP response element-binding protein (CREB) transcription.…”

Non-Excitatory Amino Acids, Melatonin, and Free Radicals: Examining the Role in Stroke and Aging

“…Additionally, astrocytes in this region display elongated and polarized processes with an increased GFAP expression and expression of factors involved in extracellular matrix remodeling and clustering of reactive astrocytes [410]. After ischemia and reperfusion injury, melatonin has been shown to attenuate reactive astrogliosis and glial scar formation, reduce the infarct volume, and, consequently, enhance axonal regeneration and promote neurobehavioral recovery in adult rats [411,412]. These effects of melatonin are related to a reduction in the activity of glycogen synthase kinase-3 beta (GSK-3β) and receptor-interacting serine/threonine-protein 1 kinase (RIP1K), proteins involved in astrocyte responses, after the treatment [412].…”

“…After ischemia and reperfusion injury, melatonin has been shown to attenuate reactive astrogliosis and glial scar formation, reduce the infarct volume, and, consequently, enhance axonal regeneration and promote neurobehavioral recovery in adult rats [411,412]. These effects of melatonin are related to a reduction in the activity of glycogen synthase kinase-3 beta (GSK-3β) and receptor-interacting serine/threonine-protein 1 kinase (RIP1K), proteins involved in astrocyte responses, after the treatment [412]. Furthermore, melatonin pretreatment has been shown to reduce the increased expression of Nox2 and Nox4 in astrocyte neurons and endothelial cells, reduce RONS levels, and inhibit cell apoptosis [413].…”