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

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.