2. Academic Validation
  3. Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation

Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation

  • Cell Mol Biol Lett. 2024 Aug 28;29(1):114. doi: 10.1186/s11658-024-00634-1.
Yuhua Chen # 1 2,  Wei He # 3,  Junlin Qiu 4,  Yangyang Luo 5,  Chenlong Jiang 5,  Feng Zhao 6,  Hong Wei 1,  Jiao Meng 1 2,  Tianlin Long 1,  Xin Zhang 1,  Lingjian Yang 7,  Quanhua Xu 1,  Juning Wang 2,  Chi Zhang 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Academy of Traditional Chinese Medicine, Bijie Traditional Chinese Medicine Hospital, Bijie, 551700, China.
  • 2 Department of Medical Science Research Center, Peihua University, Xi'an, 710125, Shaanxi, China.
  • 3 Department of Neurosurgery, Qilu Hospital of Shandong University (Qingdao), Qingdao, 266000, Shandong, China.
  • 4 Department of Cardiology, First Hospital of Northwestern University, Xi'an, 710043, Shaanxi, China.
  • 5 School of Life Sciences, Northwest University, Xi'an, 710069, Shaanxi, China.
  • 6 Department of Sport Medicine, Sports Medicine Institute, Peking University Third Hospital, Beijing, 100191, China.
  • 7 School of Chemistry & Chemical Engineering, Ankang University, Ankang, 725000, China.
  • 8 Department of Neurosurgery, The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Xiangya Hospital, Central South University, NO. 87 Xiangya Road, Changsha, 410008, China. zhangchi25@csu.edu.cn.
  • # Contributed equally.
PMID: 39198723 DOI: 10.1186/s11658-024-00634-1
Abstract

Background: Stroke is a type of acute brain damage that can lead to a series of serious public health challenges. Demonstrating the molecular mechanism of stroke-related neural cell degeneration could help identify a more efficient treatment for stroke patients. Further elucidation of factors that regulate microglia and nuclear factor (erythroid-derived 2)-like 1 (Nrf1) may lead to a promising strategy for treating neuroinflammation after ischaemic stroke. In this study, we investigated the possible role of pterostilbene (PTS) in Nrf1 regulation in cell and animal models of ischaemia stroke.

Methods: We administered PTS, ITSA1 (an HDAC Activator) and RGFP966 (a selective HDAC3 Inhibitor) in a mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R) and a model of microglial oxygen‒glucose deprivation/reperfusion (OGD/R). The brain infarct size, neuroinflammation and microglial availability were also determined. Dual-luciferase reporter, Nrf1 protein stability and co-immunoprecipitation assays were conducted to analyse histone deacetylase 3 (HDAC3)/Nrf1-regulated Nrf1 in an OGD/R-induced microglial injury model.

Results: We found that PTS decreased HDAC3 expression and activity, increased Nrf1 acetylation in the cell nucleus and inhibited the interaction of Nrf1 with p65 and p65 accumulation, which reduced infarct volume and neuroinflammation (iNOS/Arg1, TNF-α and IL-1β levels) after ischaemic stroke. Furthermore, the CSF1R inhibitor PLX5622 induced elimination of microglia and attenuated the therapeutic effect of PTS following MCAO/R. In the OGD/R model, PTS relieved OGD/R-induced microglial injury and TNF-α and IL-1β release, which were dependent on Nrf1 acetylation through the upregulation of HDAC3/Nrf1 signalling in microglia. However, the K105R or/and K139R mutants of Nrf1 counteracted the impact of PTS in the OGD/R-induced microglial injury model, which indicates that PTS treatment might be a promising strategy for ischaemia stroke therapy.

Conclusion: The HDAC3/Nrf1 pathway regulates the stability and function of Nrf1 in microglial activation and neuroinflammation, which may depend on the acetylation of the lysine 105 and 139 residues in Nrf1. This mechanism was first identified as a potential regulatory mechanism of PTS-based neuroprotection in our research, which may provide new insight into further translational applications of Natural Products such as PTS.

Keywords

HDAC3; Ischaemic stroke; Neuroinflammation; Nrf1 acetylation; PTS.

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