Tumor necrosis factor-alpha-induced sickness behavior is impaired by central administration of an inhibitor of c-jun N-terminal kinase
Palin, K. ...
Rationale: Tumor necrosis factor-alpha (TNFalpha) acts within the brain to induce sickness behavior, but the molecular mechanisms are still unknown. TNFalpha binding induces receptor trimerization, ...activation of c-Jun N-terminal kinase (JNK), and induction of downstream transcription factors. Objectives: We hypothesized that TNFalpha-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 TNFalpha (50 ng/mouse) to induce sickness behavior. Sickness was assessed as adecrease 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 TNFalpha. Conclusions: These findings demonstratethat D-JNKI-1 can abrogate TNFalpha-induced sickness behavior and suggest a potential therapeutic target for treating major depressive disordersthat develop on a background of cytokine-induced sickness behavior.
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