Inhibitory effect of baricitinib on microglia and STAT3 in a region with a weak blood–brain barrier in a mouse model of rheumatoid arthritis

Abstract

Objectives In patients with rheumatoid arthritis (RA), baricitinib not only improves arthritis symptom severity, but also patients’ neuropsychological symptoms, such as depression and fatigue. However, the cellular mechanisms through which baricitinib can affect neural activity is unexplored. While the blood-brain barrier (BBB) permeability of this drug remains unclear, Janus kinase inhibitors (JAKi) might reach the area postrema (AP), which is a unique brain region with a weak BBB function. Our recent study demonstrated microglial activation during experimental arthritis in the AP. Therefore, we sought to assess the effect of baricitinib on microglia in the AP using collagen-induced arthritis mouse model. Methods Microglia number and morphology in the AP were assessed by immunostaining for ionized calcium-binding adaptor molecule-1 (Iba-1). Data were collected on post-immunization day 35 (early phase) and 84 (late phase), and compared between baricitinib- and vehicle-treated mice. The effect on signal transducers and activators of transcription (STAT3) in the AP was also immunohistochemically examined. Behavioral outcomes were assessed by examining feeding behaviors and sucrose preference tests. Results In the early phase, activated microglial levels in the AP were decreased by baricitinib, accompanied by the inhibition of phosphorylated-STAT3 and recovery of food intake and sucrose preference. On the other hand, baricitinib did not affect microglial morphology in the late phase. Conclusion Our results demonstrate that baricitinib can affect brain cells, specifically microglia, in the brain region with a weak BBB and mitigate aberrant behaviors during autoimmune arthritis, pointing to the potential therapeutic effect of JAKi on brain pathologies underpinning RA.

Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons

“…In general, most systemically administered chemical compounds can barely cross the blood–brain barrier (BBB). However, using a mouse RA model, Matsushita et al showed that baricitinib acts on a part of brain where the BBB is weak [ 39 ]. In our present data, baricitinib treatment, more than celecoxib treatment, altered the pattern of gene expression in the DRG of CAIA mice in a way similar to that seen in the control group, although both treatments did improve arthritis.…”

A case for seeking sex-specific treatments in Alzheimer’s disease

“…Analysis in cancer patients has identified sex-related differences in pharmacokinetics and, in particular, slower elimination of tyrosine kinase inhibitors in females ( Huang et al, 2022 ; Özdemir et al, 2022 ). Other inhibitors of tyrosine kinases that are also in clinical trial for the treatment of AD include dasatinib, a potent inhibitor of Abl and Src and the JAK inhibitor, baricitinib ( Matsushita et al, 2023 ), although sex-related differences in the pharmacokinetics of these have not been reported.…”

Olfactory Bulbs in Arthritis Model Mouse Persistently Express Interleukin-6 before the Onset of Arthritis: Relationship to Food Intake

“…Süß et al [ 12 ] revealed the activation of microglia (using integrin subunit α-M and ionized calcium-binding adapter molecule 1 as microglial maker) in the cortex, striatum, and thalamus in tumor necrosis factor-alpha (TNF-α) transgenic mice and showed that TNF inhibitors suppressed the activation of microglia. Recently, we reported that microglia are activated in the area postrema of CIA mice and that Janus kinase signal transducers and transcription inhibitor activators suppress their activation [ 15 , 16 ]. However, it remains unclear when inflammatory changes occur in the CNS and how they spread spatially in these mouse models.…”