Berberine prevents lethal EV71 neurological infection in newborn mice

Abstract

Enterovirus 71 (EV71) is the major pathogen causing fatal neurological complications of hand, foot, and mouth disease (HFMD) in young children. Currently no effective antiviral therapy is available. In the present study, we found that natural compound Berberine (BBR) displayed potent inhibitory effects on EV71 replication in various neural cells (IC50 of 2.79–4.03 μM). In a newborn mouse model of lethal EV71 infection, Berberine at 2–5 mg/kg markedly reduced mortality and clinical scores. Consistently, the replication of EV71 and pathological changes were attenuated in various infected organs including brain and lung with BBR treatment. Interestingly, EV71 infection in the brain mainly localized in the peripheral zone of brainstem and largely in astrocytes. Primary culture of astrocytes from newborn mouse brain confirmed the efficient EV71 replication that was mostly inhibited by BBR treatment at 5 μM. Further investigations revealed remarkably elevated cellular reactive oxygen species (ROS) levels that coincided with EV71 replication in primary cultured astrocytes and various cell lines. BBR largely abolished the virus-elevated ROS production and greatly diminished EV71 replication by up-regulating NFE2 like bZIP transcription factor 2 (Nrf2) via the kelch like ECH associated protein 1 (Keap)-Nrf2 axis. The nuclear localization of Nrf2 and expression of downstream antioxidant enzymes heme oxygenase 1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were increased significantly by BBR treatment. Collectively, our findings revealed that BBR prevents lethal EV71 neurological infection via inhibiting virus replication through regulating Keap-Nrf2 axis and ROS generation in astrocytes of brainstem, thus providing a potential antiviral treatment for severe EV71 infection associated with neurological complications.

Role of the NLRP3/caspase-1/GSDMD signaling pathway in dopaminergic neurons during Japanese encephalitis virus infection

“…The present study con rmed that JEV not only replicated in the brain but also targeted DA neurons in vivo, causing decreases in the numbers of DA neurons and TH levels, affecting the secretion of dopamine, and promoting the onset of dyskinesia, con rming that JEV infection of DA neurons caused cell death. Neuroin ammation triggered by sustained action is present in infectious diseases such as JEV, enterovirus 71 (EV71) and porcine hemagglutinating encephalomyelitis virus (PHEV) [46][47][48]. The present study showed that dopaminergic neurons induced in ammation and pathological changes after JEV infection, which is consistent with the general facts.…”

Network pharmacology-based exploration identified the antiviral efficacy of Quercetin isolated from mulberry leaves against enterovirus 71 via the NF-κB signaling pathway

“…2021 ) by restoring the body’s overall balance to counteract the harmful effects of viral infections ( Chen and Ye, 2022 ). Numerous traditional Chinese medicines have been proven to possess antiviral properties ( Guan et al, 2020 ; Kang et al, 2021 ; Lee et al, 2021 ; Cui et al, 2022 ) capable of directly acting on viruses and stimulating the immune system to induce interferon production, thereby indirectly inactivating viruses ( Huang et al, 2022 ).…”

Anti‐inflammatory, antioxidant, and immunomodulatory effects of Berberis vulgaris and its constituent berberine, experimental and clinical, a review

“…Berberine (200 mg/kg, i.g., for 2 weeks) prevents brain tissue against ischemia–reperfusion injury damage induced by middle cerebral artery occlusion through decreasing MDA and nitric oxide levels and increasing SOD activity (Chu et al, 2017). Berberine (2 and 5 mg/kg, i.p., for 1 week) prevents lethal neurological infection caused by Enterovirus 71 (EV71) by inhibiting virus replication by the regulation of the Keap‐Nrf2 axis and ROS generation in astrocytes of the brainstem in newborn mice (Cui et al, 2022). Berberine (5 and 50 mg/kg, i.p., for 1 week) significantly protected gastric mucosa that induced by ethanol in mice by increasing expression of eNOS mRNA and inhibiting expression of iNOS mRNA (Pan et al, 2005).…”

“…Berberine may have potential applications for the prevention and treatment of viral and bacterial infections. ROS generation in astrocytes of the brainstem in newborn mice (Cui et al, 2022). Berberine (5 and 50 mg/kg, i.p., for 1 week) significantly protected gastric mucosa that induced by ethanol in mice by increasing expression of eNOS mRNA and inhibiting expression of iNOS mRNA (Pan et al, 2005).…”