The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

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

  • Se Hwan Park (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Support Center, Inje University) ;
  • Jeong Rim Ko (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Support Center, Inje University) ;
  • Jin Han (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Support Center, Inje University)
  • Received : 2023.11.27
  • Accepted : 2024.01.22
  • Published : 2024.03.01
Download PDF
⟨ Previous Next ⟩

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. Eight-week-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 synapse-related proteins including synapsin-1 and -2 were significantly reduced in the Cis-CON 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.

Keywords

Acknowledgement

This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation (NRF) of Korea (grant number NRF-2021R1C1C2013256); Cardiovascular and Metabolic Disease Core Research Support Center (2023R1A6C101B008); and National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number NRF-2022R1I1A1A01053891).

References

  1. Whitney KA, Lysaker PH, Steiner AR, Hook JN, Estes DD, Hanna NH. Is "chemobrain" a transient state? A prospective pilot study among persons with non-small cell lung cancer. J Support Oncol. 2008;6:313-321.
  2. Gan HK, Bernstein LJ, Brown J, Ringash J, Vakilha M, Wang L, Goldstein D, Kim J, Hope A, O'Sullivan B, Waldron J, Abdul Razak AR, Chen EX, Siu LL. Cognitive functioning after radiotherapy or chemoradiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2011;81:126-134.
  3. Skoogh J, Steineck G, Stierner U, Cavallin-Stahl E, Wilderang U, Wallin A, Gatz M, Johansson B; Swenoteca. Testicular-cancer survivors experience compromised language following chemotherapy: findings in a Swedish population-based study 3-26 years after treatment. Acta Oncol. 2012;51:185-197.
  4. Erfani Majd N, Shahraki R, Tabandeh MR, Hosseinifar S. Protective effects of Aloe vera gel on cisplatin-induced oxidative stress, apoptosis and neurons structure in rat hippocampus. Vet Res Forum. 2022;13:111-119.
  5. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364-378.
  6. Ghosh S. Cisplatin: the first metal based anticancer drug. Bioorg Chem. 2019;88:102925.
  7. Fung C, Dinh P Jr, Ardeshir-Rouhani-Fard S, Schaffer K, Fossa SD, Travis LB. Toxicities associated with cisplatin-based chemotherapy and radiotherapy in long-term testicular cancer survivors. Adv Urol. 2018;2018:8671832.
  8. Zhou W, Kavelaars A, Heijnen CJ. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLoS One. 2016;11:e0151890.
  9. Das A, Ranadive N, Kinra M, Nampoothiri M, Arora D, Mudgal J. An overview on chemotherapy-induced cognitive impairment and potential role of antidepressants. Curr Neuropharmacol. 2020;18:838-851.
  10. Umfress A, Speed HE, Tan C, Ramezani S, Birnbaum S, Brekken RA, Sun X, Plattner F, Powell CM, Bibb JA. Neuropathological effects of chemotherapeutic drugs. ACS Chem Neurosci. 2021;12:3038-3048.
  11. Yoo KH, Tang JJ, Rashid MA, Cho CH, Corujo-Ramirez A, Choi J, Bae MG, Brogren D, Hawse JR, Hou X, Weroha SJ, Oliveros A, Kirkeby LA, Baur JA, Jang MH. Nicotinamide mononucleotide prevents cisplatin-induced cognitive impairments. Cancer Res. 2021;81:3727-3737.
  12. Langella S, Sadiq MU, Mucha PJ, Giovanello KS, Dayan E; Alzheimer's Disease Neuroimaging Initiative. Lower functional hippocampal redundancy in mild cognitive impairment. Transl Psychiatry. 2021;11:61.
  13. Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129:154-169.
  14. Koronyo-Hamaoui M, Gaire BP, Frautschy SA, Alvarez JI. Editorial: role of inflammation in neurodegenerative diseases. Front Immunol. 2022;13:958487.
  15. Englander EW. DNA damage response in peripheral nervous system: coping with cancer therapy-induced DNA lesions. DNA Repair (Amst). 2013;12:685-690.
  16. Wang D, Wang B, Liu Y, Dong X, Su Y, Li S. Protective effects of ACY-1215 against chemotherapy-related cognitive impairment and brain damage in mice. Neurochem Res. 2019;44:2460-2469.
  17. Datta Chaudhuri A, Dasgheyb RM, DeVine LR, Bi H, Cole RN, Haughey NJ. Stimulus-dependent modifications in astrocyte-derived extracellular vesicle cargo regulate neuronal excitability. Glia. 2020;68:128-144.
  18. Upadhya R, Zingg W, Shetty S, Shetty AK. Astrocyte-derived extracellular vesicles: neuroreparative properties and role in the pathogenesis of neurodegenerative disorders. J Control Release. 2020;323:225-239.
  19. John JP, Sunyer B, Hoger H, Pollak A, Lubec G. Hippocampal synapsin isoform levels are linked to spatial memory enhancement by SGS742. Hippocampus. 2009;19:731-738.
  20. Yang R, Chang Q, Meng X, Gao N, Wang W. Prognostic value of systemic immune-inflammation index in cancer: a meta-analysis. J Cancer. 2018;9:3295-3302.
  21. Silva MS, de Andrade Gomes Y, de Sousa Cavalcante ML, Telles PVN, da Silva ACA, Severo JS, de Oliveira Santos R, Dos Santos BLB, Cavalcante GL, Rocha CHL, Palheta-Junior RC, de Cassia Meneses Oliveira R, Dos Santos RF, Sabino JPJ, Dos Santos AA, Tolentino Bento da Silva M. Exercise and pyridostigmine prevents gastric emptying delay and increase blood pressure and cisplatin-induced baroreflex sensitivity in rats. Life Sci. 2021;267:118972.
  22. Almeida AA, Correia TML, Pires RA, Silva DAD, Coqueiro RS, Machado M, Magalhaes ACM, Queiroz RF, Soares TJ, Pereira R. Nephroprotective effect of exercise training in cisplatin-induced renal damage in mice: influence of training protocol. Braz J Med Biol Res. 2022;55:e12116.
  23. Seo DY, Bae JH, Zhang D, Song W, Kwak HB, Heo JW, Jung SJ, Yun HR, Kim TN, Lee SH, Kim AH, Jeong DH, Kim HK, Han J. Effects of cisplatin on mitochondrial function and autophagy-related proteins in skeletal muscle of rats. BMB Rep. 2021;54:575-580.
  24. Nan X, Sun Q, Xu X, Yang Y, Zhen Y, Zhang Y, Zhou H, Fang H. Forsythoside B ameliorates diabetic cognitive dysfunction by inhibiting hippocampal neuroinflammation and reducing synaptic dysfunction in ovariectomized mice. Front Aging Neurosci. 2022;14:974690.
  25. Mille-Hamard L, Billat VL, Henry E, Bonnamy B, Joly F, Benech P, Barrey E. Skeletal muscle alterations and exercise performance decrease in erythropoietin-deficient mice: a comparative study. BMC Med Genomics. 2012;5:29.
  26. Garcia JM, Scherer T, Chen JA, Guillory B, Nassif A, Papusha V, Smiechowska J, Asnicar M, Buettner C, Smith RG. Inhibition of cisplatin-induced lipid catabolism and weight loss by ghrelin in male mice. Endocrinology. 2013;154:3118-3129.
  27. Conte E, Bresciani E, Rizzi L, Cappellari O, De Luca A, Torsello A, Liantonio A. Cisplatin-induced skeletal muscle dysfunction: mechanisms and counteracting therapeutic strategies. Int J Mol Sci. 2020;21:1242.
  28. Lin MT, Ko JL, Liu TC, Chao PT, Ou CC. Protective effect of D-methionine on body weight loss, anorexia, and nephrotoxicity in cisplatin-induced chronic toxicity in rats. Integr Cancer Ther. 2018;17:813-824.
  29. Amiri A, Chovanec M, Oliva V, Sedliak M, Mego M, Ukropec J, Ukropcova B. Chemotherapy-induced toxicity in patients with testicular germ cell tumors: the impact of physical fitness and regular exercise. Andrology. 2021;9:1879-1892.
  30. Den H, Dong X, Chen M, Zou Z. Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer's disease or mild cognitive impairment - a meta-analysis of randomized controlled trials. Aging (Albany NY). 2020;12:4010-4039.
  31. Kolliker-Frers R, Udovin L, Otero-Losada M, Kobiec T, Herrera MI, Palacios J, Razzitte G, Capani F. Neuroinflammation: an integrating overview of reactive-neuroimmune cell interactions in health and disease. Mediators Inflamm. 2021;2021:9999146.
  32. Lv H, Wang S, Tian M, Wang L, Gao J, Zhao Q, Li Z, Jia X, Yu Y. Exercise preconditioning ameliorates cognitive impairment in mice with ischemic stroke by alleviating inflammation and modulating gut microbiota. Mediators Inflamm. 2022;2022:2124230.
  33. Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020;9:42.
  34. Mann CN, Devi SS, Kersting CT, Bleem AV, Karch CM, Holtzman DM, Gallardo G. Astrocytic α2-Na+/K+  ATPase inhibition suppresses astrocyte reactivity and reduces neurodegeneration in a tauopathy mouse model. Sci Transl Med. 2022;14:eabm4107.
  35. de Senna PN, Xavier LL, Bagatini PB, Saur L, Galland F, Zanotto C, Bernardi C, Nardin P, Goncalves CA, Achaval M. Physical training improves non-spatial memory, locomotor skills and the blood brain barrier in diabetic rats. Brain Res. 2015;1618:75-82.
  36. Chupel MU, Minuzzi LG, Furtado G, Santos ML, Hogervorst E, Filaire E, Teixeira AM. Exercise and taurine in inflammation, cognition, and peripheral markers of blood-brain barrier integrity in older women. Appl Physiol Nutr Metab. 2018;43:733-741.
  37. Medhat E, Rashed L, Abdelgwad M, Aboulhoda BE, Khalifa MM, El-Din SS. Exercise enhances the effectiveness of vitamin D therapy in rats with Alzheimer's disease: emphasis on oxidative stress and inflammation. Metab Brain Dis. 2020;35:111-120.
  38. Wang YY, Zhou YN, Jiang L, Wang S, Zhu L, Zhang SS, Yang H, He Q, Liu L, Xie YH, Liang X, Tang J, Chao FL, Tang Y. Long-term voluntary exercise inhibited AGE/RAGE and microglial activation and reduced the loss of dendritic spines in the hippocampi of APP/PS1 transgenic mice. Exp Neurol. 2023;363:114371.
  39. Magee JC, Grienberger C. Synaptic plasticity forms and functions. Annu Rev Neurosci. 2020;43:95-117.
  40. Lu C, Gao R, Zhang Y, Jiang N, Chen Y, Sun J, Wang Q, Fan B, Liu X, Wang F. S-equol, a metabolite of dietary soy isoflavones, alleviates lipopolysaccharide-induced depressive-like behavior in mice by inhibiting neuroinflammation and enhancing synaptic plasticity. Food Funct. 2021;12:5770-5778.
  41. Lin L, Yang SS, Chu J, Wang L, Ning LN, Zhang T, Jiang Q, Tian Q, Wang JZ. Region-specific expression of tau, amyloid-β protein precursor, and synaptic proteins at physiological condition or under endoplasmic reticulum stress in rats. J Alzheimers Dis. 2014;41:1149-1163.
  42. Mirza FJ, Zahid S. The role of synapsins in neurological disorders. Neurosci Bull. 2018;34:349-358.
  43. Tassan Mazzocco M, Guarnieri FC, Monzani E, Benfenati F, Valtorta F, Comai S. Dysfunction of the serotonergic system in the brain of synapsin triple knockout mice is associated with behavioral abnormalities resembling synapsin-related human pathologies. Prog Neuropsychopharmacol Biol Psychiatry. 2021;105:110135.
  44. Li SM, Li B, Zhang L, Zhang GF, Sun J, Ji MH, Yang JJ. A complement-microglial axis driving inhibitory synapse related protein loss might contribute to systemic inflammation-induced cognitive impairment. Int Immunopharmacol. 2020;87:106814.
  45. Bilchak JN, Caron G, Cote MP. Exercise-induced plasticity in signaling pathways involved in motor recovery after spinal cord injury. Int J Mol Sci. 2021;22:4858.
  46. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011;11:607-615.
  47. He XF, Liu DX, Zhang Q, Liang FY, Dai GY, Zeng JS, Pei Z, Xu GQ, Lan Y. Voluntary exercise promotes glymphatic clearance of amyloid beta and reduces the activation of astrocytes and microglia in aged mice. Front Mol Neurosci. 2017;10:144.
  48. Rizzo FR, Guadalupi L, Sanna K, Vanni V, Fresegna D, De Vito F, Musella A, Caioli S, Balletta S, Bullitta S, Bruno A, Dolcetti E, Stampanoni Bassi M, Buttari F, Gilio L, Mandolesi G, Centonze D, Gentile A. Exercise protects from hippocampal inflammation and neurodegeneration in experimental autoimmune encephalomyelitis. Brain Behav Immun. 2021;98:13-27.
  49. Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, Goncalves RA, Clarke JR, Beckman D, Staniszewski A, Berman H, Guerra LA, Forny-Germano L, Meier S, Wilcock DM, de Souza JM, Alves-Leon S, Prado VF, Prado MAM, Abisambra JF, et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med. 2019;25:165-175.
  50. Zare Z, Zarbakhsh S, Tehrani M, Mohammadi M. Neuroprotective effects of treadmill exercise in hippocampus of ovariectomized and diabetic rats. Neuroscience. 2022;496:64-72.
  51. Navazani P, Vaseghi S, Hashemi M, Shafaati MR, Nasehi M. Effects of treadmill exercise on the expression level of BAX, BAD, BCL-2, BCL-XL, TFAM, and PGC-1α in the hippocampus of thimerosal-treated rats. Neurotox Res. 2021;39:1274-1284.
  52. Vanzella C, Neves JD, Vizuete AF, Aristimunha D, Kolling J, Longoni A, Goncalves CAS, Wyse ATS, Netto CA. Treadmill running prevents age-related memory deficit and alters neurotrophic factors and oxidative damage in the hippocampus of Wistar rats. Behav Brain Res. 2017;334:78-85.
  53. Rasoolijazi H, Norouzi Ofogh S, Ababzadeh S, Mehdizadeh M, Shabkhiz F. Comparing the effects of rosemary extract and treadmill exercise on the hippocampal function and antioxidant capacity in old rats. Basic Clin Neurosci. 2021;12:361-372.