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

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.