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Effects of long-term infliximab and tocilizumab treatment on anxiety-like behavior and cognitive function in naive rats

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Abstract

Background

Circulating cytokines have been proposed to be implicated in the development of mood disorders and cognitive impairment. This study aims to examine the effect of chronic treatment with infliximab, a tumor necrosis factor-alpha (TNF-alpha) inhibitor, and tocilizumab, an antibody against interleukin-6 (IL-6) receptor on anxiety-like behavior and cognitive function.

Methods

Twenty-eight male, Wistar rats were randomly allocated into negative control, vehicle, infliximab and tocilizumab groups. After 8 weeks of intraperitoneal drug administration, rats performed the elevated-plus maze, the elevated-zero maze, the olfactory social memory and the passive avoidance tests. Brain sections at the level of the hippocampus, the amygdala and the prefrontal cortex were histologically examined. Finally, hippocampal and amygdaloid brain-derived neurotrophic factor (BDNF) expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

Results

Infliximab group exhibited a significantly higher number of entries and time spent into the open arms of the mazes, showing a lower level of anxiety. In the olfactory social memory test, tocilizumab significantly increased the ratio of interaction. Both infliximab- and tocilizumab-treated animals had a significantly lower latency time in the passive avoidance test that suggests an improved memory. Histological examination revealed similar morphology and neuronal density between groups. BDNF expression levels were significantly increased in the groups receiving anti-cytokine treatment.

Conclusions

Our findings suggest that long-term peripheral TNF-alpha and IL-6 inhibition improves anxiety and cognitive function in rats and leads to an increased BDNF expression in the brain.

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Abbreviations

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

CNS:

Central nervous system

CTRL group:

Negative control group

DG:

Dentate gyrus

H&E:

Hematoxylin and eosin

HPA axis:

Hypothalamic–pituitary–adrenal axis

HDIPs:

Head dips over the edge of the maze

IDO:

Indoleamine 2,3-dioxygenase

IL-6:

Interleukin-6

INFX group:

Infliximab group

LSD:

Least significant difference

One-way ANOVA:

One-way analysis of variance

POCD:

Postoperative cognitive dysfunction

RT-qPCR:

Reverse transcription-quantitative polymerase chain reaction

SAPs:

Stretched attend postures

TCZ group:

Tocilizumab group

TNF-alpha:

Tumor necrosis factor-alpha

VEH group:

Vehicle group

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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.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloníki, Greece

    Frideriki Poutoglidou, Chryssa Pourzitaki, Foteini Malliou, Athanasios Saitis, Ioannis Tsimoulas, Spyridon Panagiotopoulos & Dimitrios Kouvelas

  2. Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, University Campus, 54124, Thessaloníki, Greece

    Maria Eleni Manthou

  3. Department of Clinical Pharmacology, School of Health Sciences, Aristotle University of Thessaloniki, PO Box 1532, 54006, Thessaloníki, Greece

    Frideriki Poutoglidou

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  1. Frideriki Poutoglidou
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  2. Chryssa Pourzitaki
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  8. Dimitrios Kouvelas
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Contributions

FP: data curation, investigation, methodology, writing original draft. CP: formal analysis, investigation, methodology, writing—review and editing. MEM, FM, AS and SP: investigation, methodology. IT: data curation, investigation. DK: conceptualization, project administration, supervision.

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Correspondence to Frideriki Poutoglidou.

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Poutoglidou, F., Pourzitaki, C., Manthou, M.E. et al. Effects of long-term infliximab and tocilizumab treatment on anxiety-like behavior and cognitive function in naive rats. Pharmacol. Rep 74, 84–95 (2022). https://doi.org/10.1007/s43440-021-00328-x

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