Abstract
Cell death is deeply involved in pathophysiology of brain injury after intracerebral hemorrhage (ICH). Necroptosis, one of the recently discovered forms of cell death, plays an important role in various diseases, including ICH. Previous studies have suggested that a considerable number of neurons undergoes necroptosis after ICH. However, necroptosis of microglia after ICH has not been reported to date. The present study demonstrated for the first time that necroptosis occurred in the microglia surrounding the hematoma after ICH in C57 mice, and melatonin, a hormone that is predominantly synthesized in and secreted from the pineal gland, exerted a neuroprotective effect by suppressing this process. When we further explored the potential underlying mechanism, we found that melatonin inhibits RIP3-mediated necroptosis by regulating the deubiquitinating enzyme A20 (also known as TNFAIP3) expression after ICH. In summary, we have demonstrated the role of microglial necroptosis in the pathogenesis of ICH. More importantly, A20 was identified as a novel target of melatonin, which opens perspectives for future research.
Highlights
Intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality worldwide
When we further explored the potential underlying mechanism, we found that melatonin inhibits receptor-interacting protein 3 (RIP3)-mediated necroptosis by regulating the deubiquitinating enzyme A20 expression after ICH
We demonstrated that melatonin inhibits necroptosis of microglia after ICH, thereby reducing brain edema and improving neurological function in the acute phase of ICH
Summary
Intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality worldwide. Primary injuries after ICH are usually caused by the mechanical damage of the hematoma to the surrounding brain tissues. Secondary injuries, including inflammation and cell death, are extensively involved in the pathological processes following hemorrhagic events [4]. Cell death is a hallmark of secondary brain injury after ICH [5]. Numerous experimental and clinical observations indicate a variety of cell death forms and mechanisms take place during hemorrhagic stroke [6]. Among them, programmed cell death is highly correlated with the homeostatic mechanisms of the nervous system. Necroptosis, known as programmed necrosis, shares upstream signaling elements with apoptosis, such as tumor necrosis factor (TNF), Fas-associated death domain (FADD), and Toll-like receptor (TLR) [7].
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