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.

Neuropathic pain (NP) refers to pains induced by injury or disease involving the somatosensory system, which severely threatens physical and mental health of patients. Although pathogenesis of NP is uncertain, evidence has been provided for involvement of inflammation and oxidative stress (OS) in NP. G protein-coupled receptor (GPR173) is a converted GPCR, with Phoenixin 14 (PHN-14) as its ligand. Recent studies have revealed the neuroprotective property of PHN-14. Our study explored pharmacological effect of PHN-14 on NP. A chronic constriction injury (CCI) model was established in rats, followed by administering 60 mg/kg PHN-14 and 10 mg/kg pregabalin daily. As expected, the Gpr173 was downregulated in CCI rats. Reduced PWMT and PWTL values, increased serum potassium levels, and elevated serum C-reactive protein (CRP) and Calcitonin gene-related peptide (CGRP) levels were all observed in the CCI rats, all of which were significantly rescued by PHN-14 and pregabalin. Moreover, elevated malondialdehyde (MDA) and catalase (CAT) levels, repressed superoxide dismutase (SOD) activity, and upregulated Nrf2 perceived in CCI rats were abolished by PHN-14 and pregabalin. Lastly, the high levels of inflammatory mediators and activated NF-κB signaling in the CCI rats were greatly suppressed by PHN-14 and pregabalin. Collectively, the NP and chronic inflammation in CCI rats were alleviated by PHN-14, which is an agonist of GPR173.