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

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-3 beta) 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-3 beta and RIP1K activities.

Automated summary

Melatonin has long-term benefits on cerebral damage after ischemia and reperfusion injury, as it reduces infarct volume, neuronal cell death, reactive astrogliosis, and glial scar formation, while promoting axonal regeneration and neurobehavioral recovery. By inhibiting the activities of GSK-3 beta and RIP1K, melatonin effectively counteracts the deleterious effects due to astrocyte responses and improves functional recovery during the chronic phase of cerebral ischemia and reperfusion injury.