Qingkailing injection ameliorates cerebral ischemia-reperfusion injury and modulates the AMPK/NLRP3 Inflammasome Signalling pathway

Abstract

BackgroundCerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide. Qingkailing (QKL) injection, a patented Chinese medicine approved by the China Food and Drug Administration, has been widely used in clinical practice to treat cerebral ischemia in China. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is activated in cerebral ischemia and thus, is an effective therapeutic target. AMP-activated protein kinase (AMPK) is an important regulator inhibiting NLRP3 inflammasome activation.MethodsWe investigated the potential of QKL injection to provide neuroprotection after cerebral ischemia in a rat model of middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats (210–230 g) were randomly divided into three groups which consist of sham, MCAO and 3 ml/kg QKL. Rats in the QKL group received intraperitoneal injections of 3 ml/kg QKL, while rats in other groups were given saline in the same volumes. After 90 min ischemia and 24 h reperfusion, neurological function, laser speckle imaging, brain infarction, brain water content and brain blood barrier permeability were examined and cell apoptosis at prefrontal cortex were evaluated 24 h after MCAO, and western blot and real-time quantitative polymerase chain reaction was also researched, respectively.ResultsIntraperitoneal administration of QKL alleviated neurological deficiencies, cerebral infarction, blood-brain barrier permeability, brain oedema and brain cell apoptosis after MCAO induction. QKL decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and increased anti-inflammatory cytokines, IL-4 and IL-10. Furthermore, QKL activated phosphorylated AMPK, decreased oxidative stress and decreased NLRP3 inflammasome activation.ConclusionsQKL relieved cerebral ischemia reperfusion injury and suppressed the inflammatory response by inhibiting AMPK-mediated activation of the NLRP3 inflammasome. These results suggest that QKL might have potential in treating brain inflammatory response and attenuating the cerebral ischemia-reperfusion injury.

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“…Ischemia/reperfusion injury is considered as a brain and blood vessel complication trigged by the thrombolysis treatment to ischemic stroke, which has given a severe threat to human health and happiness. Recent research studies have shown that several traditional Chinese medicines and edible plants, such as Qingkailing injection [ 16 ], Yiqi Tongluo granule [ 17 ], and Crepidiastrum denticulatum extract [ 18 ], could relieve ischemia/reperfusion injury. Punica granatum L. is an edible fruit with plenty of bioactivities for hundreds of years.…”

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“…AMPK is mainly responsible for peripheral energy balance, fat metabolism and ATP conservation and synthesis. 35 AMPK has frequently been referred to as the "metabolic master switch", and it has the ability to be rapidly activated by anti-inflammatory stimuli. 13 When the cell energy supply is reduced, AMPK can be activated to enhance energy production 14 and represents a potential protective mechanism in the early stages of cerebral ischemia.…”

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“…Besides, CIRI could stimulate dangerous molecular signals in the body, stimulate extracellular and intracellular pattern recognition receptor signals, thus inducing excessive release of inflammatory mediators, leading to neuronal apoptosis. 31 TNF-α and IL-6 are typical representatives of proinflammatory factors, which will aggravate the inflammatory injury of CIRI. IL-10 is an anti-inflammatory medium that helps prevent inflammation.…”