Attenuation of adjuvant-induced arthritis with carnosic acid by inhibiting mPGES-1, COX-2, and bone loss in male SD rats

Abstract

Objective

Rheumatoid arthritis (RA), a chronic inflammatory disease, is characterized by joint swelling, cartilage erosion, and bone destruction. This study investigated the therapeutic efficacy of Carnosic acid (CA), a natural compound with anti-inflammatory and antioxidant properties, in an adjuvant-induced arthritis model.

Methods

Paw swelling and arthritis index were measured. Oxidative stress markers, including lipid peroxidation and antioxidant enzyme levels, were assessed. Synovial tissue was analyzed for pro-inflammatory markers using real-time Q-PCR and Western blotting. The expression of mPGES-1 was determined by Western blotting. Peripheral neuropathic pain was assessed using cold and mechanical allodynia tests. Bone loss was quantitatively assessed through microcomputed tomography (μCT) scanning of femurs and X-ray radiography. Indomethacin-induced gastric ulcers were evaluated. Molecular docking studies were conducted to analyze the binding affinity of CA to mPGES-1.

Results

The CA treatment not only demonstrated a significant reduction in joint inflammation and paw swelling but also mitigated oxidative stress and improved the antioxidant defence system. CA inhibited microsomal prostaglandin E synthase-1 (mPGES-1) expression and the expression of pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenases-2 (COX-2), thus attenuating the arthritis symptoms without severe gastrointestinal side effects. Additionally, it inhibited the expression of pro-inflammatory molecules such as iNOS and COX-2, contributing to the reduction of arthritis symptoms. Notably, CA treatment prevented the common side effects of traditional RA treatments like corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), including weight loss, bone degradation, and gastric ulcers.

Conclusions

These findings suggest that CA, through specific enzyme inhibition, offers a compelling alternative therapeutic approach for RA. Further research is warranted to explore the potential of CA in other arthritis models and its suitability for human RA treatment.

HIGHLIGHTS

1. CA significantly reduces inflammation in FCA induced arthritis model.

2. CA treatment inhibits key pro-inflammatory molecules, including mPGES-1 and COX-2

3. In silico docking studies confirm the affinity of CA to mPGES-1.

4. CA prevents bone loss and avoids side effects seen with standard treatments.

5. Antioxidant properties of CA counteract oxidative stress related to chronic inflammation.

Keywords:

• Anti-inflammatory therapies
• carnosic acid
• enzyme inhibition
• inflammation
• oxidative stress
• rheumatoid arthritis

Acknowledgements

The authors wish to express their profound gratitude to the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India. We also extend our appreciation to our colleagues and lab members whose contributions and constructive feedback have been instrumental in the successful completion of this work. We are deeply grateful for everyone’s efforts.

Author contribution

Shweta S.: Investigation, Writing - review & editing. Tribhuvan B.: Investigation, Writing - Original Draft, Sunil K.: Software, Methodology. Bijo M.: Software, Validation, Writing - review & editing. Manish K.J.: Methodology, Formal analysis, Data Curation, Visualization, Project administration, Writing - Review & Editing V.G.M. Naidu: Conceptualization, Resources, Supervision, Funding acquisition, Writing - review & editing.

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

No specific grant was received for this work, but research work is carried out by a common institute fund provided by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilisers, Government of India.