Effect of a TNF-Alpha Inhibitor on Anxiety and Depression-Like Behaviors in a Mouse Chemobrain Model

Abstract

Although chemotherapy increases the survival rate of cancer patients, it causes significant side effects such as deterioration in cognitive functions that generate a decline in their living standards. In our study, the effect of adalimumab on anxiety- and depression-like behaviors in mice with cognitive impairment with methotrexate was investigated. In our study, methotrexate (40 mg kg-1) was administered intraperitoneally as a single dose to create a chemobrain model in mice. Adalimumab (10 mg kg-1), a TNF-alpha inhibitor, was administered twice, 1 hour and 5 days before methotrexate administration. Anxiety-like behaviors were measured with elevated plus maze test and open field test, depression-like behaviors were measured with tail suspension test, and hippocampal tissue was examined histopathologically. Methotrexate decreased the time spent in the central zone in the open-field arena, the time spent in the open arms in the elevated plus maze test, and increased the duration of immobility in the tail suspension test in rats. Methotrexate caused a decrease in the number of neuronal cells in the CA3 region of the hippocampus, as well as neurodegenerative and atrophic changes. Adalimumab ameliorated methotrexate-related anxiety- and depression-like behaviors, and caused improvement in histopathological changes. In this study, it was shown that methotrexate-related anxiety and depression-like behavioral disorders were prevented by adalimumab treatment, but further studies are recommended to investigate the mechanisms mediating the therapeutic effect of adalimumab.

Keywords

• Methotrexate
• adalimumab
• anxiety
• depression
• neuroinflammation

References

1. 1. Taillibert S, Voillery D, Bernard-Marty C. Chemobrain: is systemic chemotherapy neurotoxic? Curr Opin Oncol. 2007; 19(6):623-27.
2. 2. Schrappe M, Reiter A, Riehm H. Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia. J Neurooncol. 1998; 38(2-3):159-65.
3. 3. Strober BE, Menon K. Folate supplementation during methotrexate therapy for patients with psoriasis. J Am Acad Dermatol. 2005; 53(4):652-59.
4. 4. Argyriou AA, Assimakopoulos K, Iconomou G, Giannakopoulou F, Kalofonos HP. Either called “chemobrain” or “chemofog,” the long-term chemotherapy-induced cognitive decline in cancer survivors is real. J Pain Symptom Manage. 2011; 41(1):126-39.
5. 5. Lv S, Wu N, Wang Q, Yang LH. Endogenous hydrogen sulfide alleviates methotrexate-induced cognitive impairment by attenuating endoplasmic reticulum stress-induced apoptosis via CHOP and caspase-12. Fundam Clin Pharmacol. 2020; 34(5):559-70.
6. 6. Sritawan N, Suwannakot K, Naewla S, et al. Effect of metformin treatment on memory and hippocampal neurogenesis decline correlated with oxidative stress induced by methotrexate in rats. Biomed Pharmacother. 2021; 144:112280.
7. 7. Wu LL, Lin DN, Yu LH, Yang LH. Endoplasmic reticulum stress plays an important role in methotrexate-related cognitive impairment in adult rats. Int J Clin Exp Pathol. 2017; 10(10):10252-60.
8. 8. Alexander TC, Simecka CM, Kiffer F, et al. Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model. Behav Brain Res. 2018; 346:21-28.

9. 9. Sirichoat A, Anosri T, Kaewngam S, et al. Neuroprotective properties of chrysin on decreases of cell proliferation, immature neurons and neuronal cell survival in the hippocampal dentate gyrus associated with cognition induced by methotrexate. Neurotoxicology. 2022; 92:15-24.
10. 10. Sritawan N, Prajit R, Chaisawang P, et al. Metformin alleviates memory and hippocampal neurogenesis decline induced by methotrexate chemotherapy in a rat model. Biomed Pharmacother. 2020; 131:110651.
11. 11. Sirichoat A, Krutsri S, Suwannakot K, et al. Melatonin protects against methotrexate-induced memory deficit and hippocampal neurogenesis impairment in a rat model. Biochem Pharmacol. 2019; 163:225-33.
12. 12. Yang M, Kim JS, Kim J, et al. Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer. Brain Res Bull. 2012; 89(1-2):50-56.
13. 13. Aslankoc R, Ozmen O, Yalcın A. Astaxanthin ameliorates damage to the cerebral cortex, hippocampus and cerebellar cortex caused by methotrexate. Biotech Histochem. 2022; 97(5):382-93.
14. 14. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010; 140(6):918-934.
15. 15. Aggarwal BB, Gupta SC, Sung B. Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. Br J Pharmacol. 2013; 169(8):1672-92.
16. 16. Kaur H, Patro I, Tikoo K, Sandhir R. Curcumin attenuates inflammatory response and cognitive deficits in experimental model of chronic epilepsy. Neurochem Int. 2015; 89:40-50.
17. 17. Xu JJ, Guo S, Xue R, et al. Adalimumab ameliorates memory impairments and neuroinflammation in chronic cerebral hypoperfusion rats. Aging. 2021; 13(10):14001-14.
18. 18. Correger E, Marcos J, Laguens G, Stringa P, Cardinal-Fernández P, Blanch L. Pretreatment with adalimumab reduces ventilator-induced lung injury in an experimental model. Rev Bras Ter Intensiva. 2020; 32(1).
19. 19. Park J, Lee SY, Shon J, et al. Adalimumab improves cognitive impairment, exerts neuroprotective effects and attenuates neuroinflammation in an Aβ1-40-injected mouse model of Alzheimer’s disease. Cytotherapy. 2019; 21(6):671-82.
20. 20. Ou W, Yang J, Simanauskaite J, et al. Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy. J Neuroinflammation. 2021; 18(1):312.
21. 21. Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: Definitions, frequency and pharmacological aspects. J Crohns Colitis. 2010; 4(4):355-66.
22. 22. Durmaz S, Kurtoğlu T, Barbarus E, Eliyatkın N, Yılmaz M. TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats. Acta Cir Bras. 2020; 35(2):e202000202.
23. 23. Wang JY, Zhang Y, Chen Y, et al. Mechanisms underlying antidepressant effect of transcutaneous auricular vagus nerve stimulation on CUMS model rats based on hippocampal α7nAchR/NF-κB signal pathway. J Neuroinflammation. 2021;18(1):291.
24. 24. Fathalizade F, Baghani M, Khakpai F, Fazli-Tabaei S, Zarrindast MR. GABA-ergic agents modulated the effects of histamine on the behaviour of male mice in the elevated plus maze test. Exp Physiol. 2022; 107(3):233-42.
25. 25. Wen J, Maxwell RR, Wolf AJ, Spira M, Gulinello ME, Cole PD. Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model. Neuropharmacology. 2018; 139:76-84.
26. 26. Berlin C, Lange K, Lekaye HC, et al. Long-term clinically relevant rodent model of methotrexate-induced cognitive impairment. Neuro Oncol. 2020; 22(8):1126-37.