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GPR39 Agonist TC-G 1008 Promoted Mitochondrial Biogenesis and Improved Antioxidative Capability via CREB/PGC-1α Pathway Following Intracerebral Hemorrhage in Mice

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Abstract

Mitochondrial dysfunction and excessive reactive oxygen species production due to impaired mitochondrial biogenesis have been proven to exacerbate secondary brain injury after intracerebral hemorrhage (ICH). The G-protein-coupled receptor 39 (GPR39) agonist TC-G 1008 has been shown to exert anti-oxidative stress effect in acute hypoxic brain injury. Herein, our study aimed to investigate the potential effects of TC-G 1008 on neuronal mitochondrial biogenesis and antioxidative stress in a mouse model of ICH and explore the underlying mechanisms. A total of 335 male C57/BL6 mice were used to establish an autologous blood-induced ICH model. Three different dosages of TC-G 1008 were administered via oral gavage at 1 h, 25 h, and 49 h post-ICH. The GPR39 siRNA and cAMP response element-binding protein (CREB) inhibitor 666–15 were administered via intracerebroventricular injection before ICH insult to explore the underlying mechanisms. Neurobehavioral function tests, Western blot, quantitative polymerase chain reaction, immunofluorescence staining, Fluoro-Jade C staining, TUNEL staining, dihydroethidium staining, transmission electron microscopy, and enzyme-linked immunosorbent assay were performed. Expression of endogenous GPR39 gradually increased in a time-dependent manner in the peri-hematoma tissues, peaking between 24 and 72 h after ICH. Treatment with TC-G 1008 significantly attenuated brain edema, hematoma size, neuronal degeneration, and neuronal death, as well as improved neurobehavioral deficits at 72 h after ICH. Moreover, TC-G 1008 upregulated the expression of mitochondrial biogenesis-related molecules, including PGC-1α, NRF1, TFAM, and mitochondrial DNA copy number, associated with antioxidative stress markers, such as Nrf2, HO-1, NQO1, SOD, CAT, and GSH-Px. Furthermore, treatment with TC-G 1008 preserved neuronal mitochondrial function and structure post-ICH. Mechanistically, the protective effects of TC-G 1008 on neuronal mitochondrial biogenesis and antioxidative stress were partially reversed by GPR39 siRNA or 666 -15. Our findings indicated that GPR39 agonist TC-G 1008 promoted mitochondrial biogenesis and improved antioxidative capability after ICH, partly through the CREB/PGC-1α signaling pathway. TC-G 1008 may be a potential therapeutic agent for patients with ICH.

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Data Availability

The data used in the present study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82201470), Chongqing Natural Science Foundation Project (No. CSTB2023NSCQ-MSX0107 and No. cstc2020jcyj-msxmX0225), and Chongqing Postdoctoral Science Foundation (No.2022CQBSHTB3097).

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Authors and Affiliations

  1. Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China

    Zhongyi Zhang, Ye Yuan, Xingyu Zhang, Yuguang Tang, Yutong Zhao, Jinyu Dai, Yihao Tao & Zongyi Xie

  2. Department of Neurosurgery, Center for Malignant Brain Tumors, National Glioma MDT Alliance, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China

    Lingui Gu

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  1. Zhongyi Zhang
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The research was conceived and designed by Zhongyi Zhang and Lingui Gu. Zhongyi Zhang, Xingyu Zhang, and Jinyu Dai conducted the research. Ye Yuan and Yuguang Tang analyzed the data. Zhongyi Zhang, Yutong Zhao, Yihao Tao, and Zongyi Xie drafted and revised the manuscript. All authors have reviewed and approved the final version of the manuscript.

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Correspondence to Yihao Tao or Zongyi Xie.

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Zhang, Z., Yuan, Y., Zhang, X. et al. GPR39 Agonist TC-G 1008 Promoted Mitochondrial Biogenesis and Improved Antioxidative Capability via CREB/PGC-1α Pathway Following Intracerebral Hemorrhage in Mice. Transl. Stroke Res. (2024). https://doi.org/10.1007/s12975-024-01240-1

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