Combined use of dasatinib and quercetin alleviates overtraining-induced deficits in learning and memory through eliminating senescent cells and reducing apoptotic cells in rat hippocampus

• Published in: Behavioural brain research 2023-02, Vol.440, p.114260-114260, Article 114260
• Main Authors: Wang, Chenkang, Kang, Yu, Liu, Panwen, Liu, Weiwei, Chen, Wenhui, Hayashi, Toshihiko, Mizuno, Kazunori, Hattori, Shunji, Fujisaki, Hitomi, Ikejima, Takashi
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cellular Senescence; Dasatinib; Dasatinib - metabolism; Dasatinib - pharmacology; Hippocampus; Hippocampus - metabolism; Maze Learning; Overtraining; Quercetin; Quercetin - pharmacology; Rats; Senescence; Senolytic
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2022.114260

Excessive physical exercise (overtraining, OT) charactered by long-term and excessive training results in the damage of multiple vital tissues including hippocampus which plays a critical role in learning and memory. A combination of dasatinib (D) plus quercetin (Q) (D+Q) belongs to senolytic drugs which selectively kill senescent cells in vitro and vivo. In this study, the rats that suffered a five-week excessive swimming training were subjected to the oral administration of D+Q. D+Q alleviated the decline in exercise performance of OT rats during the swimming training, and prevented learning and memory deficits in Morris water maze, Y-maze and novel object recognition tests after excessive swimming training. Analytical results by SA-β-gal staining and western blotting showed that D+Q significantly reduced senescent cells with repressed expression of senescence-related proteins, p53 and p21, in hippocampus. Nissl and immunohistochemical staining showed that D+Q significantly attenuated neuronal loss caused by apoptosis. Interestingly, we observed elevated level of cleaved caspase 3, an apoptosis executor protein, in p21 positive hippocampus cells by D+Q treatment in immunofluorescent staining, suggesting that senescent cells were induced to apoptosis in D+Q-treated rats. The positive control drug, silibinin, showed similar protective effect against OT, but did not induce the apoptosis of senescent cells, suggesting a difference in the protective mechanisms. These results indicated that D+Q alleviates overtraining-induced deficits in learning and memory through elimination of senescent cells and reduction of apoptotic cell number. [Display omitted] •Dasatinib + quercetin treatment prevents OT-induced learning and memory deficits.•Dasatinib + quercetin induces apoptosis of senescent cells in hippocampus.•Dasatinib + quercetin alleviates apoptotic neuronal loss in hippocampus.