Abstract
We investigated whether Xiao-Xu-Ming decoction reduced mitophagy activation and kept mitochondrial function in cerebral ischemia-reperfusion injury. Rats were randomly divided into 5 groups: sham, ischemia and reperfusion (IR), IR plus XXMD (60 g/kg/day) (XXMD60), IR plus cyclosporin A (10 mg/kg/day) (CsA), and IR plus vehicle (Vehicle). Focal cerebral ischemia and reperfusion models were induced by middle cerebral artery occlusion (MCAO). Cerebral infarct areas were measured by triphenyl tetrazolium chloride staining. Cerebral ischemic injury was evaluated by hematoxylin and eosin staining (HE) and Nissl staining. Ultrastructural features of mitochondria and mitophagy in the penumbra of the ischemic cortex were observed by transmission electron microscopy. Mitophagy was detected by immunofluorescence labeled with LC3B and VDAC1. Autophagy lysosome formation was observed by immunofluorescence labeled with LC3B and Lamp1. The expression of LC3B, Beclin1, and Lamp1 was analyzed by Western blot. The rats subjected to MCAO showed worsened neurological score and cell ischemic damage. These were all significantly reversed by XXMD or CsA. Moreover, XXMD/CsA notably downregulated mitophagy and reduced the increase in LC3, Beclin1, and Lamp1 expression induced by cerebral ischemia and reperfusion. The findings demonstrated that XXMD exerted neuroprotective effect via downregulating LC3, Beclin1, Lamp1, and mitochondrial p62 expression level, thus leading to the inhibition of mitophagy.
Highlights
Mitochondria play crucial roles in energy production, programmed cell death, calcium homeostasis, reactive oxidative phosphorylation, and cell cycle regulation [1]
Cerebral infarct areas and neurological deficits induced by cerebral ischemia and reperfusion were
The findings showed that cerebral ischemia and reperfusion resulted in a significant increase in LC3B, Beclin1, and Lamp1 expression compared with the sham control (Sham) group (p < 0 05)
Summary
Mitochondria play crucial roles in energy production, programmed cell death, calcium homeostasis, reactive oxidative phosphorylation, and cell cycle regulation [1]. The roles of autophagy in the cerebral ischemia injury have been widely studied. As one type of selective autophagy, is extremely important for maintaining mitochondrial homeostasis by removing damaged mitochondria [10]. Behavioural Neurology death and attenuated mitophagy may protect neurons from cerebral injury [16, 17]. Our previous studies have revealed that XXMD alleviates BBB disruption and protects neurovascular unit and mitochondria from cerebral injury induced by cerebral ischemia and reperfusion [19,20,21]. Whether XXMD could regulate mitophagy following cerebral ischemia and reperfusion has not been studied yet. The present study was aimed at exploring the effect of XXMD treatment on mitophagy and mitochondrial function after cerebral ischemia and reperfusion
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