2. Academic Validation
  3. Pregnane X receptor (PXR) deficiency protects against spinal cord injury by activating NRF2/HO-1 pathway

Pregnane X receptor (PXR) deficiency protects against spinal cord injury by activating NRF2/HO-1 pathway

  • CNS Neurosci Ther. 2023 Jun 2. doi: 10.1111/cns.14279.
Li-Na Xuan 1 2,  Zhen-Xin Hu 3,  Zhen-Fu Jiang 1 2,  Cong Zhang 4,  Xiao-Wan Sun 4,  Wen-Hua Ming 4,  Hui-Tao Liu 5,  Rong-Fang Qiao 4,  Lin-Jie Shen 6,  Shao-Bo Liu 1 2,  Guan-Yu Wang 1 2,  Lin Wen 4,  Zhi-Lin Luan 4 7,  Jian Yin 1 2
Affiliations

Affiliations

  • 1 Department of Neurosurgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.
  • 2 Epileptic Center of Liaoning, the Second Affiliated Hospital of Dalian Medical University, Dalian, China.
  • 3 Department of Orthopedics, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
  • 4 Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
  • 5 Department of Orthopedics, Taizhou Hospital of Zhejiang Province, Linhai, China.
  • 6 Department of Gastroenterology, Ningbo First Hospital, Ningbo, China.
  • 7 Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, China.
PMID: 37269088 DOI: 10.1111/cns.14279
Abstract

Introduction: As a devastating Neurological Disease, spinal cord injury (SCI) results in severe tissue loss and neurological dysfunction. Pregnane X receptor (PXR) is a ligand-activated nuclear receptor with a major regulatory role in xenobiotic and endobiotic metabolism and recently has been implicated in the central nervous system. In the present study, we aimed to investigate the role and mechanism of PXR in SCI.

Methods: The clip-compressive SCI model was performed in male wild-type C57BL/6 (PXR+/+ ) and PXR-knockout (PXR-/- ) mice. The N2a H2 O2 -induced injury model mimicked the pathological process of SCI in vitro. Pregnenolone 16α-carbonitrile (PCN), a mouse-specific PXR agonist, was used to activate PXR in vivo and in vitro. The siRNA was applied to knock down the PXR expression in vitro. Transcriptome sequencing analysis was performed to discover the relevant mechanism, and the NRF2 inhibitor ML385 was used to validate the involvement of PXR in influencing the NRF2/HO-1 pathway in the SCI process.

Results: The expression of PXR decreased after SCI and reached a minimum on the third day. In vivo, PXR knockout significantly improved the motor function of mice after SCI, meanwhile, inhibited Apoptosis, inflammation, and oxidative stress induced by SCI. On the contrary, activation of PXR by PCN negatively influenced the recovery of SCI. Mechanistically, transcriptome sequencing analysis revealed that PXR activation downregulated the mRNA level of heme oxygenase-1 (HO-1) after SCI. We further verified that PXR deficiency activated the NRF2/HO-1 pathway and PXR activation inhibited this pathway in vitro.

Conclusion: PXR is involved in the recovery of motor function after SCI by regulating NRF2/HO-1 pathway.

Keywords

Pregnane X receptor (PXR); activation; gene knockout; oxidative stress; spinal cord injury (SCI).

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