Treadmill exercise ameliorates chemotherapy-induced memory impairment through Wnt/β-catenin signaling pathway

Sang-Seo Park; Sang-Hoon Kim; Bo-Kyun Kim; Mal-Soon Shin; Hyun-Tae Jeong; Jong-Suk Park; Tae-Woon Kim

doi:10.12965/jer.2346594.297

Treadmill exercise ameliorates chemotherapy-induced memory impairment through Wnt/β-catenin signaling pathway

J Exerc Rehabil. 2023 Dec 26;19(6):314-319. doi: 10.12965/jer.2346594.297. eCollection 2023 Dec.

Authors

Sang-Seo Park¹, Sang-Hoon Kim^{2

3}, Bo-Kyun Kim⁴, Mal-Soon Shin⁵, Hyun-Tae Jeong⁵, Jong-Suk Park⁵, Tae-Woon Kim⁶

Affiliations

¹ Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea.
² Department of Sport and Health Sciences, College of Art and Culture, Sangmyung University, Seoul, Korea.
³ Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
⁴ Department of Emergency Technology, College of Health Science, Gachon University, Incheon, Korea.
⁵ Division of Global Sport Studies, College of Culture and Sports, Korea University, Sejong, Korea.
⁶ Department of Human Health Care, Gyeongsang National University, Jinju, Korea.

Abstract

Doxorubicin (DOX) is a widely used chemotherapy drug for various cancers and it is known to induce cognitive impairment. The aim of this study was to investigate the effect of treadmill exercise on chemotherapy-induced memory impairment. We assessed whether DOX affects inflammation, mitochondrial Ca²⁺ retention capacity, and Wnt/β-catenin signaling. Male Sprague-Dawley rats were divided into control group, exercise group, DOX-injection group, and DOX-injection and exercise group. To create a DOX-induced memory impairment model, animals were injected intraperitoneally with DOX (2 mg/kg) dissolved in saline solution once a week for 4 weeks. Treadmill exercise was performed once a day, 5 days a week, for 8 consecutive weeks. Short-term memory was determined using the step-down avoidance test. Western blot was performed for the proinflammatory cytokines, Wnt/β-catenin signaling, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) in the hippocampus. Mitochondrial Ca²⁺ retention capacity in the hippocampus was also measured. DOX-injection rats showed deterioration of short-term memory along with decreased expression of BDNF and TrkB in the hippocampus. Levels of the proinflammatory cytokines, tumor necrosis factor-α and interleukin-6, were increased in the DOX-injection rats. Wnt/β-catenin signaling was activated and mitochondrial Ca²⁺ retention capacity was decreased in the DOX-injection rats. However, treadmill exercise alleviated short-term memory impairment, decreased proinflammatory cytokines, increased BDNF and TrkB expression, and enhanced mitochondrial Ca²⁺ retention capacity. Treadmill exercise restorated Wnt/β-catenin signaling pathway. This study demonstrated that treadmill exercise can be used for patients undergoing chemotherapy with DOX.

Keywords: Doxorubicin; Mitochondrial Ca2+ retention capacity; Proinflammatory cytokine; Short-term memory; Treadmill exercise; Wnt/β-catenin signaling.