Xuesaitong Combined with Dexmedetomidine Improves Cerebral Ischemia-Reperfusion Injury in Rats by Activating Keap1/Nrf2 Signaling and Mitophagy in Hippocampal Tissue

Abstract

Ischemic stroke is the most common type of cerebrovascular disease with high mortality and poor prognosis, and cerebral ischemia-reperfusion (CI/R) injury is the main murderer. Here, we attempted to explore the effects and mechanism of Xuesaitong (XST) combined with dexmedetomidine (Dex) on CI/R injury in rats. First, a rat model of CI/R injury was constructed via the middle cerebral artery occlusion (MCAO) method and treated with XST and Dex alone or in combination. Then, on the 5th and 10th days of treatment, the neurological impairment was assessed using the modified neurological severity scores (mNSS), the 8-arm radial maze test (8ARMT), novel object recognition test (NORT), and fear conditioning test (FCT). H&E staining was performed to observe the pathological changes of the hippocampus. ELISA and related kits were used to assess the monoamine neurotransmitters and antioxidant enzyme activities in the hippocampus. The ATP, mitochondrial membrane potential levels, and qRT-PCR of genes related to mitochondrial function were determined to assess mitochondrial functions in the hippocampus and western blot to determine Keap1/Nrf2 signaling pathway and mitophagy-related protein expression. The results showed that XST combined with Dex significantly reduced mNSS, improved spatial memory and learning deficits, and enhanced fear memory and cognitive memory ability in CI/R rats, which was superior to single-drug treatment. Moreover, XST combined with Dex treatment improved hippocampal histopathological damage; significantly increased the levels of monoamine neurotransmitters, neurotrophic factors, ATP, and mitochondrial membrane potential; and upregulated the activities of antioxidant enzymes and the expression of mitophagy-related proteins in the hippocampus of CI/R rats. XST combined with Dex treatment also activated the Keap1/Nrf2 signaling and upregulated the protein expression of downstream antioxidant enzymes HO-1 and NQ. Altogether, this study showed that a combination of XST and Dex could activate the Keap1/Nrf2 signaling and mitophagy to protect rats from CI/R-related neurological impairment.

Suppression of cerebral ischemia injury induced blood brain barrier breakdown by dexmedetomidine via promoting CCN1

“…Numerous studies have shown that Dex has protective effects on heart, kidney, lung and other organs in ischemia-reperfusion animal models [ 34 ]. It has been found that Dex plays a protective role in intestinal ischemia-reperfusion injury through anti inflammation, inhibition of caspase-3 protein expression and apoptosis [ 35 ]. It was reported that Dex could attenuate neuronal injury induced by cerebral ischemia-reperfusion by regulating miR-199a [ 9 ].…”

The neuroprotective effect of Chinese herbal medicine for cerebral ischemia reperfusion injury through regulating mitophagy

“…Xuesaitong (XST), a Chinese medicinal preparation containing PNS, is widely used in the treatment of ischemic stroke. A study showed that it combined with dexmedetomidine I attenuated I/R injury by activating Keap1/Nrf2 signaling and mitophagy ( Han et al, 2022b ).…”

“…Animal and cellular experiments have further demonstrated that CHM monomers and decoctions can improve ischemic stroke symptoms and provide neuroprotection by attenuating cerebral I/R injury ( Ding et al, 2019 ; Jiao-Yan et al, 2021 ; Tang et al, 2021 ; Ni et al, 2022 ; Liao et al, 2023 ). These studies have found that many Chinese medicines, including monomers and decoctions, can attenuate cerebral I/R injury by modulating mitophagy ( Zhang et al, 2020a ; Han et al, 2022a ; Ji et al, 2022a ; Huang et al, 2023a ). Interestingly, some of these medicines work by inhibiting mitophagy, while others work by activating it.…”

Low-dose Esketamine promotes brain protection via the ERK/Nrf2 pathway in vascular dementia rats

“…The hippocampus is an essential limbic system and irreplaceable in learning, memory and cognitive function. The hippocampus is susceptible and easily damaged in cerebral ischemia, the central part of histopathological changes induced by cerebral ischemia [9]. Nuclear factor E2-related factor2 (Nrf2) can alleviate the progression of neurodegenerative diseases by regulating antioxidant defence, improving mitochondrial function, inhibiting in ammatory damage and other bene cial effects [10].…”