title: Aggression behaviour induced by oral administration of the Janus-kinase inhibitor tofacitinib, but not oclacitinib, under stressful conditions.
abstract: Janus kinase (JAK) inhibitors have recently been developed for allergic diseases. We focused on the 2 different JAK inhibitors, tofacitinib (selective for JAK3) and oclacitinib (selective for JAK1 and 2), to clarify the mechanism of anti-inflammatory and anti-itching potency of these drugs. In the process of detecting anti-itching potency, we observed that tofacitinib treated mice showed aggression behaviour. The objective of the study reported here was to investigate the aggressive behaviour induced by tofacitinib by using a mouse model of allergic dermatitis and the resident-intruder test. For the allergic dermatitis model, female BALB/c mice were sensitised and challenged topically with toluene-2,4-diisocyanate (TDI). Vehicle, tofacitinib or oclacitinib, was administered orally 30 min before TDI challenge. Scratching, aggression and standing behaviours were monitored in the 60 min period immediately following challenge of TDI. Another group of male BALB/c mice treated with vehicle, tofacitinib or oclacitinib was evaluated in the resident-intruder test and brains were obtained to determine blood brain barrier penetration. In the allergic dermatitis model, a significant increase in aggression and standing behaviour was only obvious in the tofacitinib treatment group. There was no effect in non-sensitised mice, but similar aggression was also induced by tofacitinib in male resident-intruder test. Penetration of blood-brain barrier was observed both in tofacitinib and oclacitinib treated mice. These results suggest that aggression was induced by tofacitinib under some kind of stressful environment. This study indicates a possible role of the JAK-STAT pathway in modulation of aggression behaviour.
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, NC, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Fukuyama
authors.affiliation: Institute for Anatomy and Cell Biology, Saarland University, Homburg, Saar, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.affiliation: Institute of Bioanalytical Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Institute of Bioanalytical Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Volmer
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, NC, USA. Electronic address: wolfgang_baeumer@ncsu.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bäumer
mesh_terms: D000284:Administration, Oral; D000374:Aggression / Q000187:drug effects*; D000818:Animals; D018926:Anti-Allergic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D010880:Piperidines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D011743:Pyrimidines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013315:Stress, Psychological; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000627:therapeutic use; D014051:Toluene 2,4-Diisocyanate
chemical_list: D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D014051:Toluene 2,4-Diisocyanate; C479163:tofacitinib; C588062:oclacitinib; D053612:Janus Kinases
keywords: Aggression; Janus-Kinase inhibitor; Mice; Oclacitinib; Tofacitinib