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.
Ali A Albariqi, Dalia A. Nawwar, Weam W. Ibrahim et al.· International Immunopharmaco...· 0 citations
Doxorubicin (DOX) is a highly effective anthracycline chemotherapeutic agent whose clinical utility is limited by dose-dependent cardiotoxicity. Although oxidative stress and mitochondrial injury are established mechanisms, the contribution of regulated metal-dependent cell death (MCD) pathways remains incompletely defined. This study investigated the ferroptosis and cuproptosis role in doxorubicin-induced cardiotoxicity (DIC) and evaluated the protective effects of luteolin (LUT) and nanoliposomal LUT using an integrated network pharmacology and experimental validation approach in rats. Network pharmacology identified multitarget interactions linking LUT with oxidative stress, metal homeostasis, and cell death signaling pathways. In vivo, DOX administration induced marked cardiac dysfunction, elevated serum cardiac injury biomarkers, myocardial histopathological damage, and ultrastructural abnormalities. These changes were accompanied by significant cardiac iron and copper accumulation, increased malondialdehyde (MDA), depleted superoxide dismutase (SOD) and glutathione (GSH), reduced glutathione peroxidase-4 (GPX4) activity, and increased tumor protein p53 (TP53) expression. At the molecular level, DOX downregulated the ferroptosis-protective genes, SLC7A11 and SLC3A2, while upregulating the iron transport genes, transferrin receptor 1 (TFR1) and SLC39A14, together with the cuproptosis-related genes ferredoxin-1 (FDX1) and SLC31A1, while suppressing ATP7A. These changes were further supported by altered protein expression of SLC7A11, ATP7A, and TP53. LUT significantly ameliorated these functional, biochemical, molecular, and structural alterations, indicating suppression of both ferroptotic and cuproptotic signaling. Nanoliposomal LUT showed superior efficacy to free LUT across most assessed parameters. Collectively, these findings support the involvement of ferroptosis and cuproptosis related signaling in DIC and highlight LUT, particularly in nanoliposomal form, as a promising cardioprotective strategy against anthracycline toxicity.
Amina A. Farag, W. E. El gazzar, Mahmoud Mostafa et al.· Biomedicine & pharmacotherap...· 0 citations
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