PGC1-α mediated regulatory effect on mitochondrial function of PTE mitigating memory impairment in chronic unpredictable military stress exposed nice

Abstract

Objective To determine the effects and underlying mechanism of pterostilbene (PTE) on memory dysfunction in mice exposed to chronic unpredictable military stress (CUMS). Methods Thirty-six healthy 7 to 8 week-old C57BL/6J male mice were randomly divided into control group (CON), CUMS group (for 30 d) and PTE intervention group (100 mg/kg PTE, gastric infusion). Body weight and food intake of each mouse were recorded during the intervention. After the intervention, serum corticosterone concentrations were detected by ELISA, spatial memory function of mouse was detected by Morris water maze assay, ultrastructural changes of mice hippocampal neurons were observed by transmission electron microscopy, mitochondrial respiratory function of mouse hippocampus was detected by Seahorse XF HS Mini analyzer, the relative copy number of mtDNA and the expression of Pgc-1α and Tfam at mRNA level in the hippocampus were detected by RT-qPCR, and the protein level of PGC-1α was measured with Western blotting. Results Compared with the CON group, the CUMS group had significantly decreased body weight and food intake (P < 0.05), increased serum content of corticosterone (P < 0.000 1), while PTE intervention reversed above changes (P < 0.05 and P < 0.000 1, respectively). Morris water maze assay showed that the CUMS group were worse in the memory accuracy of the platform, while the PTE group had better performance. After exposure to CUMS, more lipofuscin, swollen mitochondria and disappearance of cristae were observed with transmission electron microscopy, but comparatively mild damages were found in the PTE group. Moreover, mitochondrial basal respiration (P < 0.05), maximal respiration (P < 0.001) and spare respiratory capacity (P < 0.01) in isolated hippocampal neurons were decreased after exposed to CUMS, whereas the maximal respiration (P < 0.05), ATP-linked respiration (P < 0.05) and respiratory control rate (P < 0.05) were significantly improved in the PTE group. Furthermore, the copy number of mtDNA (P < 0.01), and the expression of Pgc-1α (P < 0.000 1) and Tfam (P < 0.01) at mRNA level in the hippocampus of the CUMS group were decreased; while those phenomena were significantly elevated in the CUMS group (P < 0.05). Western blotting indicated the expression of PGC-1α was lower in the hippocampus of the CUMS group than the CON group (P < 0.01), whereas that was significantly higher in the PTE group than the CUMS group (P < 0.05). Conclusion PTE could improve the memory function of CUMS-exposed mice, which might be related with its enhancing PGC-1α expression and thus mitigating the CUMS-induced structural and functional damages in the hippocampal mitochondria.

Keywords

• pterostilbene
• chronic unpredictable military stress
• memory
• mitochondria
• pgc-1α