Anti-Inflammatory and Analgesic Effects of TRPV1 Polypeptide Modulator APHC3 in Models of Osteo- and Rheumatoid Arthritis.

Yulia A. Logashina,Viktor A. Palikov,Yaroslav A. Andreev,Nadezhda V. Tarasova,Vitaly A. Kazakov,Yulia A. Palikova,Sviatlana V. Smolskaya,Igor A. Dyachenko

doi:10.3390/md19010039

Yulia A. Logashina, Viktor A. Palikov + Show 6 more

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https://doi.org/10.3390/md19010039

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Abstract

Arthritis is a widespread inflammatory disease associated with progressive articular surface degradation, ongoing pain, and hyperalgesia causing the development of functional limitations and disability. TRPV1 channel is one of the high-potential targets for the treatment of inflammatory diseases. Polypeptide APHC3 from sea anemone Heteractis crispa is a mode-selective TRPV1 antagonist that causes mild hypothermia and shows significant anti-inflammatory and analgesic activity in different models of pain. We evaluated the anti-inflammatory properties of APHC3 in models of monosodium iodoacetate (MIA)-induced osteoarthritis and complete Freund’s adjuvant (CFA)-induced rheumatoid monoarthritis in comparison with commonly used non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, and meloxicam. Subcutaneous administration of APHC3 (0.1 mg/kg) significantly reversed joint swelling, disability, grip strength impairment, and thermal and mechanical hypersensitivity. The effect of APHC3 was equal to or better than that of reference NSAIDs. Protracted treatment with APHC3 decreased IL-1b concentration in synovial fluid, reduced inflammatory changes in joints, and prevented the progression of cartilage degradation. Therefore, polypeptide APHC3 has the potential to be an analgesic and anti-inflammatory substance for the alleviation of arthritis symptoms.

Highlights

Arthritis is an inflammatory disease characterized by articular surface degradation and ongoing pain and hyperalgesia
Application of disease-modifying anti-rheumatic drugs (DMARDs, e.g., methotrexate [7], hydroxychloroquine [8]), non-steroidal anti-inflammatory drugs (NSAIDs), and steroids leads to multiple negative side effects due to their influence on immune, endocrine, and paracrine systems, additional pharmaceutical compounds are applied for arthritis treatment
Joint diameter in groups treated with APHC3 at doses of 0.1 and 1 mg/kg did not differ from the control group (Figure 1a and Figure S1a,b)

Summary

Introduction

Arthritis is an inflammatory disease characterized by articular surface degradation and ongoing pain and hyperalgesia. RA is a chronic and systemic autoimmune disease affecting multiple symmetric joints It is characterized by progressive disability and multiple systemic complications, such as cardiovascular, pulmonary, psychological, and skeletal disorders, leading to premature death [4,5]. The etiology of RA is complicated and involves the production of autoantigens, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), by synovial tissue B-cells during pre-RA stage, and infiltration of synovium by mononuclear cells (activated T- and B-cells) and macrophages releasing cytokines, chemokines, adhesion molecules, matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and oxygen and nitrogen species during inflammatory stage [6]. Application of disease-modifying anti-rheumatic drugs (DMARDs, e.g., methotrexate [7], hydroxychloroquine [8]), NSAIDs, and steroids leads to multiple negative side effects due to their influence on immune, endocrine, and paracrine systems, additional pharmaceutical compounds are applied for arthritis treatment. Among them are drugs targeted to the specific pro-inflammatory cytokines, such as Anakinra, recombinant IL-1 receptor antagonist [9]; ABT-981 (lukitizumab), human anti-IL-1α/β dual immunoglobulin [10]; adalimumab, human anti-TNF-α monoclonal antibody [11,12], and many others [5,13]

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