The JAK1/2 Inhibitor Baricitinib Ameliorates Neuroinflammation and Symptoms in an Animal Model of Essential Tremor

Essential tremor (ET) is one of the most prevalent adult-onset movement disorders, which significantly impairs quality of life. So far, there are few therapeutic options with limited efficacy. This study investigated the therapeutic potential of baricitinib, a selective JAK1/2 inhibitor, in the harmaline-induced model of ET. Male Swiss mice were randomly assigned to five groups (n = 8): control, harmaline, and harmaline plus baricitinib at 10, 20, or 50 mg/kg doses. ET was induced using harmaline (10 mg/kg, i.p.). Baricitinib was administered orally daily for 14 days. Assessments included behavioral tests and cerebellar gene expression analysis of inflammatory markers (TNF-α, IL-6, NF-κB), neurotrophic factors (BDNF), ET-related targets (Lingo-1, NMDA receptor), and histopathological evaluation. Baricitinib reduced harmaline-induced tremor severity. The drug also significantly ameliorated anxiety-like behaviors in elevated plus maze and open field tests, while reducing depressive-like behavior in the tail suspension test. Passive avoidance outcomes changed in a direction suggestive of improved retention; however, the high-dose findings should be interpreted cautiously because 50 mg/kg was associated with motor coordination impairment. Molecular analyses revealed baricitinib completely normalized cerebellar pro-inflammatory cytokines TNF-α and IL-6 and suppressed NF-κB expression. The drug restored BDNF levels and reduced Lingo-1 expression. Histopathological examination also suggested reduced Purkinje cell degeneration, with 20 and 50 mg/kg doses reducing Purkinje cell degeneration to control levels. Baricitinib reduced tremor and affective behaviors in a harmaline-induced ET model, though gait abnormalities persisted. Cognitive benefits at lower doses were observed, with cautious interpretation required for the high dose due to motor effects. Molecular and histological analyses supported anti-inflammatory and neuroprotective effects, indicating selective benefits via neuroinflammatory modulation.