2. Academic Validation
  3. 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

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

  • Behav Brain Res. 2022 Dec 16;114260. doi: 10.1016/j.bbr.2022.114260.
Chenkang Wang 1,  Yu Kang 1,  Panwen Liu 1,  Weiwei Liu 1,  Wenhui Chen 1,  Toshihiko Hayashi 2,  Kazunori Mizuno 3,  Shunji Hattori 3,  Hitomi Fujisaki 3,  Takashi Ikejima 4
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China.
  • 2 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China; Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, Nakanomachi, Hachioji, Tokyo, 192-0015, Japan; Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan.
  • 3 Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan.
  • 4 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China; Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning, China. Electronic address: [email protected].
PMID: 36535433 DOI: 10.1016/j.bbr.2022.114260
Abstract

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.

Keywords

apoptosis; dasatinib; hippocampus; overtraining; quercetin; senescence; senolytic.

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