Melatonin attenuates white matter injury in mice by reducing oligodendrocyte apoptosis after subarachnoid hemorrhage

Abstract

AIM: To determine whether melatonin (MLT) mitigates white matter (WM) injury by attenuating NOD-like receptor family pyrin domain-containing 3 (NLRP3)-associated oligodendrocyte apoptosis after subarachnoid hemorrhage (SAH). MATERIAL and METHODS: SAH model C57BL/6J mice were created using an endovascular perforation technique. The mice were injected intraperitoneally with MLT at doses of 50 mg/kg, 150 mg/kg and 300 mg/kg. The animals were evaluated for neurological outcomes according to neurological score, brain water content, myelin degradation, amyloid precursor protein (APP) accumulation, apoptosis, and levels of NLRP3, caspase-1, interleukin-1β, Bcl-2, and Bcl-2-interacting mediator of cell death (Bim) expression after SAH. RESULTS: MLT at a dose of 50 mg/kg improved neurological score, alleviated brain edema, and reduced WM injury. In addition, loss of myelin basic protein (MBP) and accumulation of APP, and expression in the ipsilateral/left hemisphere were found after SAH, and were reversed by MLT treatment. NLRP3 signal activation was found in microglia and apoptosis in oligodendrocytes were observed after SAH. MLT reduced oligodendrocyte apoptosis by regulating Bim and Bcl-2. CONCLUSION: Results of this study indicated that MLT exerts a WM-protective effect in SAH pathophysiology, possibly by attenuating apoptosis in oligodendrocytes.

NBTI attenuates neuroinflammation and apoptosis partly by ENT1/NLRP3/Bcl2 pathway after subarachnoid hemorrhage in rats

“…Therefore, it is of great significance to probe into how to effectively inhibit the activation of NLRP3 inflammasome, thereby ameliorating the brain damage in SAH. [ 23,24]. Similarly, our present data showed that the inhibition of NLRP3 inflammasome was accompanied by the upregulation of Bcl2, downregulation of Bax and reduction of neuronal degeneration and apoptosis.…”

“…The NLRP3 inflammasome is an important regulator of neuronal degeneration and apoptosis. A tremendous amount of basic studies have demonstrated that the pharmacologic inhibition of NLRP3 can stimulate the expression of the antiapoptotic protein Bcl2 and block the upregulation of the pro-apoptosis protein Bax, thereby improving neurologic function after SAH in rat models [23,24]. Similarly, our present data showed that the inhibition of NLRP3 inflammasome was accompanied by the upregulation of Bcl2, downregulation of Bax and reduction of neuronal degeneration and apoptosis.…”

Early Brain Injury After Subarachnoid Hemorrhage: Incidence and Mechanisms

“…115 Stimulation of the antiapoptotic protein Bcl-2 and inhibition of the pro-apoptotic protein Bax have both been demonstrated to minimize apoptosis and improve neurological outcomes in animal models of EBI. 116 Mounting evidence has identified caspase inhibition as a promising strategy to ameliorate EBI following SAH. 117…”

Myelin sheath injury and repairment after subarachnoid hemorrhage

“…Endogenous apolipoprotein E (Apo E) may also affect the polarization of microglia through the Shc1/PI3K/Akt signaling pathway and participate in myelin sheath damage ( Peng et al, 2019 ). For apoptotic molecules, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) can destroy the myelin sheath by promoting oligodendrocyte apoptosis ( Liu et al, 2020a ).…”