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Tumor necrosis factor-α-induced sickness behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase

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Abstract

Rationale

Tumor necrosis factor-α (TNFα) acts within the brain to induce sickness behavior, but the molecular mechanisms are still unknown. TNFα binding induces receptor trimerization, activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors.

Objectives

We hypothesized that TNFα-induced sickness behavior can be blocked by a novel JNK inhibitor.

Methods

To test this idea, we used a bipartite protein consisting of a ten-amino-acid sequence of the trans-activating domain of the viral TAT protein (D-TAT) linked to a 19-amino-acid peptide that specifically inhibits JNK activation (D-JNKI-1). C57BL/6J mice were pre-treated intracerebroventricularly (i.c.v.) with D-JNKI-1 or the control peptide containing only the protein transduction domain, D-TAT. Mice were then injected centrally with an optimal amount of TNFα (50 ng/mouse) to induce sickness behavior. Sickness was assessed as a decrease in social exploration of a novel juvenile, an increase in duration of immobility and loss of body weight.

Results

Pre-treatment with D-JNKI-1 (10 ng/mouse), but not D-TAT, significantly inhibited all three indices of sickness induced by central TNFα.

Conclusions

These findings demonstrate that D-JNKI-1 can abrogate TNFα-induced sickness behavior and suggest a potential therapeutic target for treating major depressive disorders that develop on a background of cytokine-induced sickness behavior.

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Acknowledgements

This research was supported by grants from the National Institutes of Health (NIH) to K.W.K. (MH51569 and AG029573) and R.D. (MH071349 and MH079829). The authors do not have a financial relationship with sponsoring organizations.

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Correspondence to K. W. Kelley.

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Palin, K., McCusker, R.H., Strle, K. et al. Tumor necrosis factor-α-induced sickness behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase. Psychopharmacology 197, 629–635 (2008). https://doi.org/10.1007/s00213-008-1086-y

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  • DOI: https://doi.org/10.1007/s00213-008-1086-y

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