Activation of Nrf2 antioxidant signaling alleviates gout arthritis pain and inflammation.
Danyi ZengChengyu YinHuina WeiYuanyuan LiYunqin YangHuimin NieYushuang PanRuoyao XuYan TaiJunying DuJinggen LiuPing WangBoyu LiuBoyi LiuPublished in: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (2023)
Excessive deposition of monosodium urate (MSU) crystal in the joint results in gout arthritis, which triggers severe pain and affects life quality. Oxidative stress is a pivotal mechanism that contributes to etiology of gout pain and inflammation. Here we investigated whether activating Nrf2, which plays important roles in regulating endogenous antioxidant response, would attenuate gout arthritis via promoting antioxidant signaling in joint tissues. Gout arthritis model was established by intra-articular injection of MSU (500 μg/ankle) into the right ankle joint of mouse. Pharmacologically activating Nrf2 by activator oltipraz (50, 100 or 150 mg/kg, intraperitoneal) at 1 h before and 5, 23, 47 h after model establishment dose-dependently inhibited joint inflammation, mechanical and heat hypersensitivities in model mice. Oltipraz (100 mg/kg) reversed gait impairments without altering locomotor activity and reduced neutrophil infiltrations in ankle joints. In vitro studies revealed oltipraz (25 μM) inhibited MSU-induced ROS production in mouse macrophages and improved mitochondrial bioenergetics impairments caused by MSU. In vivo ROS imaging combined with biochemical assays confirmed the antioxidant effects of oltipraz on model mice. Nrf2 activation inhibited pro-inflammatory cytokine overproduction in ankle joint and attenuated the overexpression and enhancement in TRPV1 channel in DRG neurons innervating hind limb. Therapeutic effects of oltipraz were abolished by inhibiting Nrf2 or in Nrf2 knockout mice. These results suggest pharmacologically activating Nrf2 alleviates gout pain, gait impairments, inflammation and peripheral sensitization via Nrf2-dependent antioxidant mechanism. Targeting Nrf2 may represent a novel treatment option for gout arthritis.
Keyphrases
- oxidative stress
- diabetic rats
- dna damage
- uric acid
- ischemia reperfusion injury
- chronic pain
- induced apoptosis
- rheumatoid arthritis
- signaling pathway
- neuropathic pain
- pain management
- spinal cord injury
- cell death
- gene expression
- type diabetes
- spinal cord
- heat shock
- reactive oxygen species
- insulin resistance
- high throughput
- high fat diet induced
- early onset
- photodynamic therapy
- single cell
- weight loss
- toll like receptor
- weight gain
- anti inflammatory
- wild type
- high speed
- endoplasmic reticulum stress
- atomic force microscopy