Rivaroxaban Modulates TLR4/Myd88/NF-Kβ Signaling Pathway in a Dose-Dependent Manner With Suppression of Oxidative Stress and Inflammation in an Experimental Model of Depression

Abstract

Depression is a common mental illness leading to upset or anxiety, with a high incidence rate in the world. Depression can lead to suicidal thoughts and behavior. The present study aimed to evaluate the effect of the direct oral anticoagulant rivaroxaban (RVX), in the model of depression induced by chronic unpredicted mild stress (CUMS) in rats. Fifty-six male Wister rats were randomly divided into seven experimental groups (8 rats/group); Group 1: Control group given vehicle per oral (p.o.), Group 2: RVXL-control group (received rivaroxaban 20 mg/kg/day, p.o..), Group 3: RVXH-control group (received rivaroxaban 30 mg/kg/day, p.o.), Group 4: chronic unpredictable mild stress (CUMS) group, Group 5: FLX-treated CUMS group (received fluoxetine 10 mg/kg/day, p.o..), Group 6: RVXL-treated CUMS group (received rivaroxaban 20 mg/kg/day, p.o.), and Group 7: RVXH-treated CUMS group (received rivaroxaban 30 mg/kg/day, p.o.). The rats received the drugs from the first day of the experiment and continued till 4 weeks—the duration of the study. The following were measured: monoamine neurotransmitters, malondialdehyde (MDA), total nitrite/nitrate (NOx), reduced glutathione (GSH), superoxide dismutase (SOD), Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor‐kappa B (NF‐κB), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor-A (VEGF-A). A forced swimming test (FST) was done. Furthermore, histological changes and glial fibrillary acidic protein (GFAP) immunoexpression were evaluated. CUMS showed a significant decrease in hypothalamic neurotransmitters, hippocampal GSH, SOD, BNDF, and VEGF-A with a significant increase in hippocampal MDA, NOx, NF-kβ, Myd88, TLR4, TNF-α, and GFAP immunoexpression. RVX showed significant improvement in all parameters (p-value < 0.0001). In conclusion, RVX in a dose-dependent manner possesses potent ameliorative effects against depression by reducing the oxidative stress and inflammatory process, through the regulation of the TLR4/Myd88/NF-kβ signaling pathway.

Clinical and preclinical evaluation of miR‐144‐5p as a key target for major depressive disorder

“…TLR4 signaling plays a pivotal role in stress‐induced neuroinflammation and MDD 53,54 . NF‐κB, a critical molecule downstream of PI3K/Akt signaling, regulates the secretion of multiple cytokines 55 and acts as part of the TLR4 downstream signaling pathway 56 . In our study, miR‐144‐5p restoration alleviated behavioral dysfunctions in CUS mice, and this effect was accompanied with decreased levels of PTEN and TLR4.…”

Intermedin Reduces Oxidative Stress and Apoptosis in Ventilator-Induced Lung Injury via JAK2/STAT3

“…SOD is an antioxidant enzyme that scavenges superoxide anion free radicals and protects cells from damage caused by oxygen free radicals. MDA is a product formed by the reaction between lipids and oxygen free radicals, and its content represents the degree of lipid peroxidation ( Abdelzaher et al, 2021 ). In the current study, we used frozen sections to detect the level of ROS in mouse lung tissue, flow cytometry to detect ROS content, and ELISA to detect the levels of SOD and MDA; we found that IMD could inhibit the oxidative stress in VILI.…”

Diosgenin relieves oxaliplatin-induced pain by affecting TLR4/NF-κB inflammatory signaling and the gut microbiota

“…30 Oxidative stress stimulates numerous intracellular signaling pathways and causes the production of pro-inflammatory cytokines. 31 It is known that the brain is more vulnerable to oxidative stress than any other organ because of its higher oxygen consumption, higher lipid content and weaker antioxidant defense. 32 When cells are exposed to oxidative stress, NF-κB can be activated and phosphorylated into the nucleus, and then up-regulate pro-inflammatory cytokines such as TNF-α.…”