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Dexmedetomidine exerts cerebral protective effects against cerebral ischemic injury by promoting the polarization of M2 microglia via the Nrf2/HO-1/NLRP3 pathway

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Abstract

Introduction

Cerebral ischemic injury is associated with long-term disability. Dexmedetomidine (Dex) can exert neuroprotective effects on cerebral ischemic/reperfusion injury. The present study explored the mechanism of Dex in cerebral ischemic injury.

Materials and methods

To this end, the permanent middle cerebral artery occlusion (p-MCAO) mouse model was established and treated with Dex or/and Nrf2 inhibitor ML385. Subsequently, microglia were subjected to oxygen–glucose deprivation (OGD) in sugar-free environment and thereafter treated with Dex, Nrf2 inhibitor, and NLRP3 lentiviral overexpression vector, respectively.

Results

Dex alleviated the neurobehavioral deficit of p-MCAO mice, reduced brain water content, relieved pathological changes, and reduced cerebral infarction size. Dex promoted the polarization of microglia from M1 to M2, thus ameliorating oxidative stress and inflammatory responses. Our results showed that Dex promoted M2-polarization of microglia in vivo and in vitro by promoting HO-1 expression via Nrf2 nuclear import. Moreover, the Nrf2/HO-1 axis inhibited the activation of NLRP2 inflammasome and NLRP3 overexpression reversed the effect of Dex.

Conclusion

In conclusion, Dex promoted M2-polarization of microglia and attenuated oxidative stress and inflammation, and thus protected against cerebral ischemic injury by activating the Nrf2/HO-1 pathway and inhibiting NLRP3 inflammasome.

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Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

Research Foundation of the Second Affiliated Hospital of Harbin Medical University (KYBS2015-02); Postdoctoral Research Fund of Heilongjiang Province (LBH-Z15139); Heilongjiang Health and Family Planning Commission Research Project (2017-078).

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Author notes

  1. Ning Wang and Huan Nie contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150081, Heilongjiang, China

    Ning Wang, Huan Nie, Yueyue Zhang, Huiying Han, Shan Wang, Wenjuan Liu & Kuo Tian

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  1. Ning Wang
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  2. Huan Nie
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Correspondence to Wenjuan Liu or Kuo Tian.

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Wang, N., Nie, H., Zhang, Y. et al. Dexmedetomidine exerts cerebral protective effects against cerebral ischemic injury by promoting the polarization of M2 microglia via the Nrf2/HO-1/NLRP3 pathway. Inflamm. Res. 71, 93–106 (2022). https://doi.org/10.1007/s00011-021-01515-5

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