Berberine attenuates ischemia–reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation

Authors: Jun-rong Zhu1,2,3,3,3,3,4,5,6,7, Hai-dan Lu1,2, Chao Guo4, Wei-rong Fang1, Hong-dong Zhao5, Jun-shan Zhou5, Feng Wang6, Yan-li Zhao1,2, Yun-man Li1, Ying-dong Zhang1,5, Chang-qing Yang1, Jian-guo Sun7
1 School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
2 Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
4 Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
5 Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
6 Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
7 Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
Correspondence to: Ying-dong Zhang:, Chang-qing Yang:, Jian-guo Sun:,
DOI: 10.1038/s41401-018-0160-1
Advance online: 28 September 2018


Inflammatory damage plays an important role in cerebral ischemic pathogenesis and represents a new target for treatment of stroke. Berberine is a natural medicine with multiple beneficial biological activities. In this study, we explored the mechanisms underlying the neuroprotective action of berberine in mice subjected transient middle cerebral artery occlusion (tMCAO). Male mice were administered berberine (25, 50 mg/kg/d, intragastric; i.g.), glycyrrhizin (50 mg/kg/d, intraperitoneal), or berberine (50 mg/kg/d, i.g.) plus glycyrrhizin (50 mg/kg/d, intraperitoneal) for 14 consecutive days before tMCAO. The neurological deficit scores were evaluated at 24 h after tMCAO, and then the mice were killed to obtain the brain samples. We showed that pretreatment with berberine dose-dependently decreased the infarct size, neurological deficits, hispathological changes, brain edema, and inflammatory mediators in serum and ischemic cortical tissue. We revealed that pretreatment with berberine significantly enhanced uptake of 18F-fluorodeoxyglucose of ischemic hemisphere comparing with the vehicle group at 24 h after stroke. Furthermore, pretreatment with berberine dose-dependently suppressed the nuclear-to cytosolic translocation of high-mobility group box1
(HMGB1) protein, the cytosolic-to nuclear translocation of nuclear factor kappa B (NF-κB) and decreased the expression of TLR4 in ischemic cortical tissue. Moreover, co-administration of glycyrrhizin and berberine exerted more potent suppression on the HMGB1/TLR4/NF-κB pathway than berberine or glycyrrhizin administered alone. These results demonstrate that berberine protects the brain from ischemia–reperfusion injury and the mechanism may rely on its anti-inflammatory effects mediated by suppressing the activation of HMGB1/TLR4/NF-κB signaling.
Keywords: berberine; glycyrrhizin; ischemic stroke; inflammation; HMGB1; TLR4; NF-κB

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