Baricitinib ameliorates behavioral deficits and NLRP3-related neuroinflammation in a ketamine rat model of schizophrenia: Role of JAK2/STAT3 and PI3K/AKT/mTOR signaling.
Ali A Albariqi, Dalia A Nawwar, Weam W Ibrahim, Mahmoud M. Khattab
International Immunopharmacology August 19, 2026 DOI: 10.1016/j.intimp.2026.117303 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Ketamine-induced rat model of schizophrenia |
| Interventions | Baricitinib Ketamine |
| Dose | Ketamine 30 mg/kg intraperitoneal for 5 days; baricitinib 5 or 20 mg/kg/day orally for 14 days |
| Duration | 5-day ketamine induction followed by 14-day baricitinib treatment |
| Topics | Ketamine Esketamine |
| Keywords | Schizophrenia Neuroinflammation Pi3k/akt/mtor Jak2/stat3 Baricitinib |
| Key points | Baricitinib, particularly at 20 mg/kg/day, attenuated ketamine-induced behavioral deficits, restored D2R expression, suppressed FGF9, NLRP3, and pro-inflammatory cytokines, and normalized JAK2/STAT3 and PI3K/AKT/mTOR signaling in rat hippocampus and prefrontal cortex. The authors suggest baricitinib may be a promising therapeutic candidate for neuroimmune dysregulation associated with schizophrenia-like alterations. |
Abstract
Baricitinib, a selective JAK1/JAK2 inhibitor with established anti-inflammatory properties, has demonstrated therapeutic efficacy in several autoimmune and inflammatory diseases. This study aimed to investigate the neuroprotective potential of baricitinib in a ketamine-induced rat model of schizophrenia. Specifically, the study examined its effects on behavioral deficits, neurochemical alterations, and neuroinflammatory responses, while exploring the association of the JAK2/STAT3 and PI3K/AKT/mTOR signaling pathways with its neuroprotective effects. Schizophrenia-like symptoms were induced by intraperitoneal administration of ketamine (30 mg/kg) for five consecutive days, followed by oral treatment with baricitinib (5 or 20 mg/kg/day) for 14 days. Ketamine administration produced significant locomotor hyperactivity, social withdrawal, and cognitive impairment, accompanied by reduced dopamine D2 receptor (D2R), contrary to elevating fibroblast growth factor 9 (FGF9), NLRP3 expression, and pro-inflammatory cytokines including interleukin-1β, interleukin-6, and tumor necrosis factor-α in both the hippocampus and prefrontal cortex. These changes were associated with marked hyperactivation of the JAK2/STAT3 and PI3K/AKT/mTOR pathways. Treatment with baricitinib, particularly at the higher dose (20 mg/kg), significantly attenuated behavioral deficits, restored D2R expression, suppressed FGF9 and NLRP3 levels, reduced pro-inflammatory cytokine production, and normalized aberrant signaling pathway activation. Histological analysis further confirmed preservation of neuronal integrity in both brain regions. These findings indicate that baricitinib exerts robust neuroprotective effects in a ketamine model of schizophrenia, accompanied by attenuation of neuroinflammation and modulation of the JAK/STAT and PI3K/AKT/mTOR pathways. The present results suggest that baricitinib may represent a promising therapeutic candidate for mitigating neuroimmune dysregulation associated with schizophrenia-like alterations.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 3
- Sex difference alters the behavioral and cognitive performance in a rat model of schizophrenia induced by sub-chronic ketamine. Journal of Psychiatric Research October 1, 2024
- Sigma-1 Receptor Activation by Fluvoxamine Ameliorates ER Stress, Synaptic Dysfunction and Behavioral Deficits in a Ketamine Model of Schizophrenia. Journal of Neuroimmune Pharmacology July 25, 2025
- Niacin mitigates blood-brain barrier tight junctional proteins dysregulation and cerebral inflammation in ketamine rat model of psychosis: Role of GPR109A receptor. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 8, 2022