Tetrahydropyrimidine-5-carboxylate attenuates experimentally induced inflammation through regulation of inflammatory and oxidative stress biomarkers in Wistar rats

Background: Rheumatoid arthritis is a chronic autoimmune disorder that causes severe pain and inflammation that gradually destroys joints. Objectives: Tetrahydropyrimidine-5-carboxylate (THP) has been investigated for its anti-inflammatory and anti-arthritic effects using both in vitro and in vivo approaches. Methods: In vitro anti-inflammatory activity of THP was assessed using protein denaturation and membrane stabilization assays at various concentrations. For in vivo anti-inflammatory activity, carrageenan-induced paw edema and xylene-induced ear edema models were performed in rats. For anti-arthritic potential, all rats except normal control group, were given an injection of Complete Freund's Adjuvant (CFA; 0.15 mL) into the left hind paw on day one. Treatment with THP at 25, 50 and 100 mg/kg was started orally from 8th day till 28th day. Methotrexate (1 mg/kg) was the standard treatment; the normal and disease groups received vehicle. The effects of treatment on body weight, paw edema, pain, blood chemistry, neurotransmitters and oxidative stress biomarkers were assessed. Results: THP exhibited significant In-vitro and in-vivo anti-inflammatory potential in dose dependent manner. THP (25-100mg/kg) treatment significantly decreased paw edema, arthritic index and pain, while restoring body weight, muscular strength, oxidative stress biomarkers and blood parameters in treated rats compared with the disease control. Treatment with THP notably modulated the mRNA expression of RANKL, OPG, MMP-13, COX-2, TNF-?, IL-6 and IL-4 compared with disease control, as evidenced by histology of the ankle joint of treated rats. THP-treated rats exhibited higher levels of serotonin and noradrenaline in sciatic nerve homogenates. Conclusion: The results showed that THP had significant dose-dependent anti-inflammatory, anti-arthritic, antioxidant and analgesic effects, suggesting that it could be a safe therapy for inflammatory and arthritic diseases, as it showed an LD50 > 2000mg/kg.