Berberine Attenuates Cerebral Ischemia-Reperfusion Injury Induced Neuronal Apoptosis by Down-Regulating the CNPY2 Signaling Pathway

Abstract

Berberine (BBR) has a neuroprotective effect against ischemic stroke, but its specific protective mechanism has not been clearly elaborated. This study explored the effect of BBR on the canopy FGF signaling regulator 2 (CNPY2) signaling pathway in the ischemic penumbra of rats. The model of cerebral ischemia-reperfusion injury (CIRI) was established by the thread embolization method, and BBR was gastrically perfused for 48 h or 24 h before operation and 6 h after operation. The rats were randomly divided into four groups: the Sham group, BBR group, CIRI group, and CIRI + BBR group. After 2 h of ischemia, followed by 24 h of reperfusion, we confirmed the neurologic dysfunction and apoptosis induced by CIRI in rats (p < 0.05). In the ischemic penumbra, the expression levels of CNPY2-regulated endoplasmic reticulum stress-induced apoptosis proteins (CNPY2, glucose-regulated protein 78 (GRP78), double-stranded RNA-activated protein kinase-like ER kinase (PERK), C/EBP homologous protein (CHOP), and Caspase-3) were significantly increased, but these levels were decreased after BBR treatment (p < 0.05). To further verify the inhibitory effect of BBR on CIRI-induced neuronal apoptosis, we added an endoplasmic reticulum-specific agonist and a PERK inhibitor to the treatment. BBR was shown to significantly inhibit the expression of apoptotic proteins induced by endoplasmic reticulum stress agonist, while the PERK inhibitor partially reversed the ability of BBR to inhibit apoptotic protein (p < 0.05). These results confirm that berberine may inhibit CIRI-induced neuronal apoptosis by downregulating the CNPY2 signaling pathway, thereby exerting a neuroprotective effect.

9-O-Terpenyl-Substituted Berberrubine Derivatives Suppress Tumor Migration and Increase Anti-Human Non-Small-Cell Lung Cancer Activity

“…Berberine not only contributes to cancer therapy but also has reported benefits in the treatment of inflammation, diabetes, and pathogenic infection and can attenuate acute renal injury and neurodegenerative diseases [34][35][36][37][38][39]. We synthesized B4 and B5 from berberrubine, derived from berberine; both B4 and B5 exert higher anti-NSCLC activities than berberine and berberrubine.…”

Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cerebral Ischemia/Reperfusion Injury

“…During ERS, the binding partner of CNPY2 changes from GRP78 to PERK, resulting in activation of the PERK-CHOP pathway and promotion of apoptosis ( Urra and Hetz, 2017 ). Inhibition of the CNPY2 signaling pathway can block neuronal apoptosis induced by CIRI, leading to neuroprotection ( Zhao et al, 2021 ). In addition, a study showed that the transcription of CHOP is regulated by ATF6 ( Yoshida et al, 2000 ).…”

Plant-Derived Compounds as Promising Therapeutics for Vitiligo

“…Berberine (BBR, ( Figure 7C ) natural isoquinoline alkaloid, is a major compound isolated from the Chinese herb Coptis chinensis Franch. ( Wang et al, 2021d ), and studies have found that BBR has pharmacological activities against cancer, hypolipidemic, cardiovascular, anti-inflammatory, and antioxidant stress ( Zhao et al, 2021 ). Wei et al studied the potential medicinal value of berberine in vitiligo.…”