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.
Highlights
Cerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide
The cerebral ischemia-reperfusion injury resulting Blood brain barrier (BBB) leakage caused an increase in brain water content (Vs Sham, p = 0.0024)
There is a significant difference among these groups (F (2, 15) = 2.166, p = 0.0015), as shown in Fig. 2c, QKL administration led to a decrease in brain oedema in the ipsilateral hemisphere, and the difference was not significant (Vs middle cerebral artery occlusion (MCAO), p > 0.05)
Summary
Cerebral ischemia is the second-leading cause of death and the main cause of permanent adult disabilities worldwide. Cerebral Ischemia is the second-leading cause of death behind ischemic heart disease, and is the main cause of permanent adult disabilities worldwide [1, 2]. Following a transient blockage of cerebral blood flow, dangerous molecular signals are released from dead or dying cells [5]. These signals, known as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), stimulate the initial activation of innate immune responses during the progression of cerebral ischemia via extracellular and intracellular pattern recognition receptors (PRRs). Inflammasomes are activated by some PRR signals, induce maturation and secretion of some inflammatory cytokines, and initiate cell pyroptosis, a form of programmed inflammatory cell death [6]
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