Minocycline Suppresses NLRP3 Inflammasome Activation in Experimental Ischemic Stroke

Abstract

Objective: Minocycline, a tetracycline antibiotic, has shown anti-inflammatory effects in cerebral ischemia and neurodegenerative disease; however, the molecular mechanisms underlying this effect have not been clearly identified. Since NLRP3 inflammasome activation controls the maturation and release of proinflammatory cytokines, especially interleukin-1β (IL-1β) and IL-18 in ischemia stroke, we suppose that minocycline may be involved in the regulation of NLRP3 inflammasome activation. Methods: We investigated the effects of minocycline on NLRP3 inflammasome activation using the transient middle cerebral artery occlusion (tMCAO) mouse model and an in vitro oxygen-glucose deprivation/reoxygenation injury model in BV2 microglial cells. Results: We found that minocycline administrated 1 h after reperfusion can improve neurological disorder, reduce infarct volume, and alleviate cerebral edema. Meanwhile, we showed that minocycline prevented the activation of microglias and attenuated NLRP3 inflammasome signaling after tMCAO injury. Furthermore, we found that the pretreatment of minocycline significantly inhibited signal 1 and signal 2 of NLRP3 inflammasome activation in BV2 cells. Conclusion: We demonstrated that minocycline can ameliorate ischemia-induced brain damage via inhibiting NLRP3 inflammasome activation.

Estradiol inhibits NLRP3 inflammasome in fibroblast‐like synoviocytes activated by lipopolysaccharide and adenosine triphosphate

“…Many regulation factors of NLRP3 inflammasomes are being studied, such as A20 negatively regulated NLRP3, clematichinenoside AR‐inhibited succinate accumulation affected by tumor growth factor‐β1, including estrogen, which was related with the development of knee OA. The regulation of estrogen on NLRP3 inflammasome had been studied in several diseases, whereas the underlying mechanism was undefined.…”

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

“…In cerebrovascular diseases, several agents taking advantage of inhibiting the NLRP3 inflammasome have been presented in the alleviation of ischemic or hemorrhagic stroke. For the treatment of ischemic stroke, it was reported that pretreatment of minocycline, a tetracycline antibiotic, significantly prevented the activation of microglia through the inhibition of the NLRP3 inflammasome in the two steps of activation, thus improving neurological disorder, reducing infarct volume and alleviating cerebral edema ( Lu et al, 2016 ). Additionally, a recent study demonstrated the neuroprotective effects of sinomenin, a kind of alkaloid derived from Sinomenium acutum , in mice cerebral artery occlusion (MCAO) ischemic models in vivo and oxygen glucose deprivation (OGD)-treated in vitro models ( Qiu et al, 2016 ).…”

Evidence and perspective for the role of the NLRP3 inflammasome signaling pathway in ischemic stroke and its therapeutic potential (Review)

“…Therefore, early inhibition of the NLRP3 inflammasome pathway may be a beneficial and reasonable choice. On the other hand, using animal models, some anti-neuroinflammation agents have been demonstrated to protect ipsilateral brain against ischemic injury up to 7 days following ischemic induction (109)(110)(111), which highlights the long-term effect and application prospect of immunotherapy. Of note, intermittent fasting has been reported to attenuate NLRP3 pathway activity and repair damaged tissues up to 4 months following ischemic stroke (112).…”