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Infliximab and Tocilizumab Reduce Anxiety-Like Behaviour and Improve Cognitive Performance in a Juvenile Collagen–Induced Arthritis Rat Model

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Abstract

Anxiety disorders and cognitive decline are highly prevalent in rheumatic diseases, including Juvenile Idiopathic Arthritis (JIA). In this study, we investigated the effect of long-term treatment with infliximab and tocilizumab on anxiety-like behaviour and cognitive performance in a juvenile collagen–induced arthritis (CIA) rat model. Forty-nine rats with established moderate arthritis were randomly allocated into 7 equal groups: negative control, vehicle, methotrexate, infliximab, tocilizumab, methotrexate + infliximab and methotrexate + tocilizumab groups. Behavioural tests were performed to evaluate anxiety-like behaviour and cognitive function. Neuropathological changes were investigated by histological examination at the level of the hippocampus, the amygdala and the prefrontal cortex. Also, the expression of Brain-Derived Neurotrophic Factor (BDNF), a biomarker associated with neuronal survival and plasticity, was determined in the hippocampus and the amygdala by RT-qPCR. We found that both infliximab and tocilizumab reduced anxiety-like behaviour in the elevated-plus and elevated-zero maze tests. Tocilizumab, also, improved cognitive function in the olfactory social memory and passive avoidance tests. Anti-cytokine treatment reversed the histopathological changes in the brain induced by CIA. BDNF expression was higher in all treatment groups and especially those receiving monoclonal antibodies combined with methotrexate. Our data provide evidence that chronic infliximab and tocilizumab treatment reduces anxiety-like behaviour, improves cognitive function, reverses neuropathological changes and increases central BDNF expression in a juvenile arthritis rat model. These findings may be translated to humans to address behavioural comorbidities associated with JIA.

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AVAILABILITY OF DATA AND MATERIAL

The data underlying this article will be shared on reasonable request to the corresponding author.

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ACKNOWLEDGEMENTS

We thank Athanasia Pappa, president of the Hellenic League Against Rheumatism, for her contribution during various stages of the research project. We also thank Roche Hellas for providing tocilizumab.

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F.P., A.S. and F.M. performed the in vivo and in vitro experiments. F.P. drafted the original manuscript and conducted the statistical analysis. She is the guarantor. C.P. contributed to the conception and design of the study, reviewed and edited the manuscript. M.E.M. performed the histological examination of the samples. D.K. contributed to the conception and design of the study and supervised the project. All authors critically reviewed and approved the final manuscript. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

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Correspondence to Frideriki Poutoglidou.

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The study was approved by the Directorate of Veterinary Services of the Region of Central Macedonia according to national legislation (Presidential Decree 56/2013, in conformance with the European Directive (2010/63/EU) (reference number: 668476(3484) 21643(87), 06/10/2019).

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Poutoglidou, F., Pourzitaki, C., Manthou, M.E. et al. Infliximab and Tocilizumab Reduce Anxiety-Like Behaviour and Improve Cognitive Performance in a Juvenile Collagen–Induced Arthritis Rat Model. Inflammation 45, 445–459 (2022). https://doi.org/10.1007/s10753-021-01560-6

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