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Salidroside Reduces Inflammation and Brain Injury After Permanent Middle Cerebral Artery Occlusion in Rats by Regulating PI3K/PKB/Nrf2/NFκB Signaling Rather than Complement C3 Activity

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Abstract

Salidroside, an active constituent of Rhodiola rosea, is neuroprotective after transient middle cerebral artery occlusion (tMCAO). However, its effects in other experimental stroke models are less understood. Here, we investigated the effect of daily intraperitoneal injections of salidroside in rats after permanent MCAO (pMCAO). Cerebral infarct volumes at 1 day after pMCAO were significantly reduced by treatment with 100 mg/kg/day salidroside, but not by 25 or 50 mg/kg/day, and this benefit of salidroside increased significantly over at least 7 days of treatment, when it was also accompanied by decreased neurological deficit scores. These observations led us to investigate the underlying mechanism of action of salidroside. 100 mg/kg salidroside for 1 day increased NeuN, Nrf2, and its downstream mediator HO-1, while it reduced nuclear NFκB p50, IL-6, and TNFα. Brusatol, a Nrf2 inhibitor, blocked the actions of salidroside on Nrf2, NFκB p50, IL-6, and TNFα. Salidroside also increased the ratio of p-PKB/PKB at 1 day after pMCAO even in the presence of brusatol. LY294002, a PI3K inhibitor, prevented all these effects of salidroside, including those on NeuN, p-PKB/PKB, Nrf2, HO-1, and pro-inflammatory mediators. In contrast, salidroside had no significant effect on the level of cerebral complement C3 after pMCAO, or on the activity of C3 as measured by the expression of cerebral Egr1. Our findings therefore suggest that salidroside reduces neuroinflammation and neural damage by regulating the PI3K/PKB/Nrf2/NFκB signaling pathway after pMCAO, and that this neuroprotective effect does not involve modulation of complement C3 activity.

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Acknowledgments

The authors thank the staff in the Animal Center of the Fujian University of TCM for their technical support.

Funding

This work was supported by the National Natural Science Foundation of China (projects 81473382 and 81603323), by the Collaborative Innovation Center for Rehabilitation Technology of Fujian University of TCM, and by the TCM Rehabilitation Research of SATCM (X2018002-Collaborative).

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  1. X. Zhang and W. Lai contributed equally to this work.

Authors and Affiliations

  1. Centre of Biomedical Research & Development, Fujian University of Traditional Chinese Medicine, No. 1 Huatou Road, Minhou Shangjie, Fuzhou, China

    X. Zhang, W. Lai, X. Ying, L. Xu, K. Chu, J. Brown, L. Chen & G. Hong

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Zhang, X., Lai, W., Ying, X. et al. Salidroside Reduces Inflammation and Brain Injury After Permanent Middle Cerebral Artery Occlusion in Rats by Regulating PI3K/PKB/Nrf2/NFκB Signaling Rather than Complement C3 Activity. Inflammation 42, 1830–1842 (2019). https://doi.org/10.1007/s10753-019-01045-7

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