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Natural and synthetic potential drug leads for rheumatoid arthritis probing innovative target: mitochondrial
Urooj Iqbal1,2, Abdul Malik3, Liza Ibrahim4
1Department of Pharmacology, College of Pharmacy, University of Sargodha, Sargodha, Pakistan.
Abstract:
Rheumatoid arthritis (RA) is an autoimmune, chronic, inflammatory disease characterized by synovial hyperplasia, bone erosion, progressive joint deterioration, and excruciating joint pain. Worldwide RA prevalence is approximately 0.1-2%, affecting women and elderly population. Limited knowledge of disease pathogenesis causes hindrance in diagnosis and treatment of RA. Deep investigation of RA pathogenesis is deemed, for the development of novel therapies. Among diverse targets for RA, proper functioning of mitochondria is essential for endurance of synovial cells and chondrocytes. Once mitochondria are damaged, these affect immune and non-immune cells in terms of their activation, survival, and differentiation prima to occurrence of RA. An innate immune complex, NLRP3 (NOD-like receptor family pyrin domain-containing 3) inflammasome plays pivotal role in RA pathogenesis through its control on the synthesis of pro-inflammatory cytokines (IL-1β & IL-18) and induction of pyroptotic cell death. Mitochondrial dysfunction is the possible primary cause of NLRP3 inflammasome activation, leading to inflammation and joint destruction in RA. This review emphasizes that how mitochondrial dysregulation affect NLRP3 inflammasome activation and contribute to RA's inflammatory cascade. It also investigates synthetic and natural substances including Berberine, Ebselen, and Resveratrol that have emerged as promising drug leads for RA by modulating mitochondrial dysfunction and inhibiting NLRP3 inflammasome activation. Furthermore, it concise the evidences from RA-associated animal models explaining beneficial impact of various therapeutic agents in attenuation of inflammation and deterioration of bone and cartilage. Hence, the current review stresses molecular pathways in mitochondrial dynamics and NLRP3 inflammasome activation, as an approach to hone RA treatment goals.
Insights
Mitochondrial dysfunction triggers NLRP3 inflammasome activation, driving rheumatoid arthritis (RA) inflammation and joint damage. Therapies targeting this pathway, like Berberine, show promise for RA treatment.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease with significant global prevalence, particularly affecting women and the elderly.
- Current understanding of RA pathogenesis is limited, hindering effective diagnosis and treatment development.
- Mitochondrial function is crucial for synovial cells and chondrocytes; dysfunction contributes to immune cell abnormalities seen in RA.
Purpose of the Study:
- To review the role of mitochondrial dysfunction in activating the NLRP3 inflammasome in rheumatoid arthritis.
- To explore the therapeutic potential of natural and synthetic compounds in modulating mitochondrial dysfunction and NLRP3 inflammasome activation for RA treatment.
Main Methods:
- Review of existing literature on mitochondrial dynamics, NLRP3 inflammasome activation, and rheumatoid arthritis pathogenesis.
- Investigation of therapeutic agents, including Berberine, Ebselen, and Resveratrol, for their effects on RA models.
- Analysis of evidence from animal models of RA regarding the impact of therapeutic interventions on inflammation and joint deterioration.
Main Results:
- Mitochondrial dysfunction is identified as a key initiator of NLRP3 inflammasome activation, leading to pro-inflammatory cytokine release (IL-1β, IL-18) and pyroptosis.
- Compounds like Berberine, Ebselen, and Resveratrol demonstrate potential in preclinical RA models by ameliorating inflammation and protecting against bone and cartilage damage.
- Evidence from animal studies supports the beneficial effects of these agents in attenuating RA-associated pathology.
Conclusions:
- Mitochondrial dysregulation and subsequent NLRP3 inflammasome activation are central to the inflammatory cascade in rheumatoid arthritis.
- Targeting mitochondrial pathways and NLRP3 inflammasome represents a promising strategy for developing novel RA therapeutics.
- Further research into these molecular mechanisms can refine treatment goals for rheumatoid arthritis.
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