Melatonin-mediated mitophagy protects against early brain injury after subarachnoid hemorrhage through inhibition of NLRP3 inflammasome activation

Abstract

The NLRP3 inflammasome is activated in the early period following subarachnoid hemorrhage(SAH), resulting in inflammatory responses. Recent studies have shown that activation of NLRP3 inflammasome is suppressed by autophagy, but the potential mechanism is unclear. In this study, we examined whether mitophagy was involved in the beneficial effect of melatonin and its relationship with NLRP3 inflammasome activation after SAH. In total, 130 adult-male SD rats were randomly divided into four groups: sham group, SAH + vehicle group, SAH + melatonin group, and SAH + 3-methyladenine (3-MA) + melatonin group. Brain samples were used for brain water content analysis, ROS assay, Western blot, immunohistochemistry and transmission electron microscopy. The results showed that melatonin treatment markedly increased the expression of both autophagy markers(LC3-II/LC3-I and Atg 5), and mitophagy markers(Parkin and PINK-1) following SAH induction. Additionally, melatonin treatment attenuated pathological changes in mitochondria and reduced ROS generation, which are closely related to NLRP3 inflammasome activation. Consequently, melatonin-mediated upregulation of proteins associated with mitophagy inhibited NLRP3 inflammasome activation and significantly reduced pro-inflammatory cytokine levels after SAH. Conversely, 3-MA, an autophagy inhibitor, reversed these beneficial effects of melatonin on mitophagy and the NLRP3 inflammasome. These results suggest that mitophagy-associated NLRP3 inflammasome inhibition by melatonin is neuroprotective against early brain injury post-SAH in rats.

Melatonin improves survival and respiratory activity of yeast cells challenged by alpha‐synuclein and menadione

“…Nevertheless, in many recent studies melatonin has been described as an enhancer of mitophagy (Cao et al, ; Kang, Hong, & Lee, ; Lin et al, ; Prieto‐Dominguez et al, ; Zhou et al, ). Altogether, our data confirm that the melatonin addition also enhances mitophagy in yeast, and is beneficial for the respiratory chain function, which demonstrates the existence of a conserved mechanism for melatonin into mitochondria quality control and biogenesis.…”

Melatonin in macrophage biology: Current understanding and future perspectives

“…Activation of the NLRP3 inflammasome leads to caspase‐1 activation, which switches pro‐IL‐1β to the matured IL‐1β through a complex pathway . In a number of studies performed in different systems and under various conditions recently summarized, melatonin has been shown to attenuate NLRP3 inflammasome activation (Figure E) . Collectively, melatonin inhibits the M1 macrophage polarization through STATs, NF‐κB, and NLRP3 pathways.…”

“…Question mark means that mTOR signaling in promoting M2 macrophage polarization needs further investigations studies performed in different systems and under various conditions recently summarized, 16 melatonin has been shown to attenuate NLRP3 inflammasome activation ( Figure 1E). [161][162][163][164] Collectively, melatonin inhibits the M1 macrophage polarization through STATs, NF-κB, and NLRP3 pathways.…”

Melatonin and inflammation—Story of a double‐edged blade

“…Suppression of NLRP3 activation by melatonin has been observed under various conditions. This was shown in radiation‐induced damage by radiotherapy of oral mucositis, and small intestine toxicity, in the septic heart, pyroptosis induction in adipose tissue, subarachnoid hemorrhage, acute lung injury, and cadmium hepatotoxicity . In cultured keratinocytes, exposure to elevated glucose concentrations caused NLRP3 activation, which was inhibited by melatonin, findings that were interpreted as a means for promoting wound healing in diabetics .…”