Korean J Physiol Pharmacol.  2024 Mar;28(2):145-152. 10.4196/kjpp.2024.28.2.145.

Exercise alleviates cisplatin-induced toxicity in the hippocampus of mice by inhibiting neuroinflammation and improving synaptic plasticity

• Park SH
• Ko JR
• Han J

• KMID: 2553526
• DOI: http://doi.org/10.4196/kjpp.2024.28.2.145

Abstract

Chemotherapy-induced cognitive impairment is recognized as the most typical symptom in patients with cancer that occurs during and following the chemotherapy treatment. Recently many studies focused on pharmaceutical strategies to control the chemotherapy side effects, however it is far from satisfactory. There may be a need for more effective treatment options. The aim of this study was to investigate the protective effect of exercise on cisplatin-induced neurotoxicity. Eightweek-old C57BL6 mice were separated into three group: normal control (CON, n = 8); cisplatin injection control (Cis-CON, n = 8); cisplatin with aerobic exercise (Cis-EXE, n = 8). Cisplatin was administered intraperitoneally at a dose of 3.5 mg/kg/day. The Cis-EXE group exercise by treadmill running (14–16 m/min for 45 min daily, 3 times/ week) for 12 weeks. Compared to the CON group, the cisplatin injection groups showed significant decrease in body weight and food intake, indicating successful induction of cisplatin toxicity. The Cis-CON group showed significantly increased levels of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α in the hippocampus, while the Cis-EXE group was significantly decreased in the expression of IL-6, IL-1β, and TNF-α. In addition, compared to the CON group, the levels of synapserelated proteins including synapsin-1 and -2 were significantly reduced in the CisCON group, and there was a significant difference between the Cis-CON and Cis-EXE groups. Antioxidant and apoptosis factors were significantly improved in the Cis-EXE group compared with the Cis-CON group. This study suggest that exercise could be meaningful approach to prevent or improve cisplatin-induced cognitive impairment.

Keyword

Cisplatin; Exercise; Hippocampus; Inflammation; Synaptic plasticity

Figure

• 

  Fig. 1 The experiment procedure of the study.

• 

  Fig. 2 Evaluation of cisplatin-induced toxicity. (A) Weekly change of body weight. (B) Compared to CON group, the body weight (F = 26.07, p < 0.01) and (C) food intake (F = 71.58, p < 0.01) were significantly decreased in Cis and Cis-EXE groups in 3 weeks after cisplatin injection. Values are presented as mean ± SD. CON, control (n = 8); Cis, cisplatin injection (n = 8); Cis-EXE, aerobic exercise with cisplatin injection (n = 8). One-way analysis of variance and Tukey’s post-hoc were used for statistical analysis; ***p < 0.001.

• 

  Fig. 3 Expression levels of neuroinflammation cytokines in the hippocampus after cisplatin injection. (A) Representative Western blots of neuroinflammatory markers. Significant reduction in neuroinflammatory markers (B) IL-6 (F = 19.55, p < 0.01), (C) TNF-α (F = 45.43, p < 0.01), and (D) IL-1β (F = 37.75, p < 0.01) were observed in the Cis-EXE group compared to the Cis group. However, no significant difference were found in (E) IL-10 levels. Values are presented as mean ± SD. IL-6, interleukin 6; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin 1 beta; IL-10, interleukin 10; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. CON, control (n = 8); Cis, cisplatin injection (n = 8); Cis-EXE, aerobic exercise with cisplatin injection (n = 8). Bradford assay R2 = 0.993, ImageJ gamma value = 0.50. One-way analysis of variance and Tukey’s post-hoc were used for statistical analysis; **p < 0.01, ***p < 0.001.

• 

  Fig. 4 Expression levels of synaptic plasticity-related factors in the hippocampus after cisplatin injection. (A) Representative Western blots of synapse-related proteins. Compared to the Cis group, expression of the (B) synapsin-1 protein (F = 55.46, p < 0.01) was significantly increased in Cis-EXE group. Meanwhile, no significant difference were found in (C) synapsin-2 levels. Values are presented as mean ± SD. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. CON, control (n = 8); Cis, cisplatin injection (n = 8); Cis-EXE, aerobic exercise with cisplatin injection (n = 8). Bradford assay R2 = 0.993, ImageJ gamma value = 0.50. One-way analysis of variance and Tukey’s post-hoc were used for statistical analysis; **p < 0.01, ***p < 0.001.

• 

  Fig. 5 Expression levels of antioxidant enzyme and apoptosis-related factors in the hippocampus after cisplatin injection. (A) Representative Western blots of antioxidant and apoptosis-related factors. (B) SOD was significantly increased in the Cis-EXE group compared to the Cis group (F = 57.71, p < 0.01). Despite there is no significant difference in the levels of apoptosis-related marker (C) caspase 3, there is a significant decrease in the level of (D) Bax in the Cis-EXE group compared to the Cis group (F = 31.56, p < 0.01) while there is a significant increase in (E) Bcl-2 levels (F = 20.12, p < 0.01). Values are presented as mean ± SD. SOD, super oxide dismutase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. CON, control (n = 8); Cis, cisplatin injection (n = 8); Cis-EXE, aerobic exercise with cisplatin injection (n = 8). Bradford assay R2 = 0.993, ImageJ gamma value = 0.50. One-way analysis of variance and Tukey’s post-hoc were used for statistical analysis; *p < 0.05, **p < 0.01, ***p < 0.001.

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