Analgesic and Anti-Inflammatory Effects of the Novel Semicarbazide-Sensitive Amine-Oxidase Inhibitor SzV-1287 in Chronic Arthritis Models of the Mouse

Abstract

Semicarbazide-sensitive amine oxidase (SSAO) catalyses oxidative deamination of primary amines. Since there is no data about its function in pain and arthritis mechanisms, we investigated the effects of our novel SSAO inhibitor SzV-1287 in chronic mouse models of joint inflammation. Effects of SzV-1287 (20 mg/kg i.p./day) were investigated in the K/BxN serum-transfer and complete Freund’s adjuvant (CFA)-evoked active immunization models compared to the reference SSAO inhibitor LJP-1207. Mechanonociception was assessed by aesthesiometry, oedema by plethysmometry, clinical severity by scoring, joint function by grid test, myeloperoxidase activity by luminescence, vascular leakage by fluorescence in vivo imaging, histopathological changes by semiquantitative evaluation, and cytokines by Luminex assay. SzV-1287 significantly inhibited hyperalgesia and oedema in both models. Plasma leakage and keratinocyte chemoattractant production in the tibiotarsal joint, but not myeloperoxidase activity was significantly reduced by SzV-1287 in K/BxN-arthritis. SzV-1287 did not influence vascular and cellular mechanisms in CFA-arthritis, but significantly decreased histopathological alterations. There was no difference in the anti-hyperalgesic and anti-inflammatory actions of SzV-1287 and LJP-1207, but only SzV-1287 decreased CFA-induced tissue damage. Unlike SzV-1287, LJP-1207 induced cartilage destruction, which was confirmed in vitro. SzV-1287 exerts potent analgesic and anti-inflammatory actions in chronic arthritis models of distinct mechanisms, without inducing cartilage damage.

Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

“…The multiplicity of roles for PrAO in diverse processes has made it an important therapeutic target (O'Sullivan et al, ). Inhibitors of PrAO have been reported and its inhibition is known to have anti‐inflammatory effects and to positively influence vascular health, neurodegenerative disease progress and lung fibrosis, among other conditions (Horváth et al, , Jarnicki et al, ).…”

Systemic and topical administration of spermidine accelerates skin wound healing

“…Amendola et al previously reported that excessive accumulated polyamines in the intracellular or extracellular environment are oxidatively deaminated by amine oxidase producing toxic products [36]. In addition, vascular adhesion protein-1 (VAP-1), which is present at high levels in endothelial cells, decomposes polyamines to produce H 2 O 2 and acrolein, increasing oxidative stress [37]. In the present study, the topical administration of SPD signi cantly upregulated the expression of IL-6 and TNF-α in the wound site (Fig.…”

The Neurokinin-1 Receptor Contributes to the Early Phase of Lipopolysaccharide-Induced Fever via Stimulation of Peripheral Cyclooxygenase-2 Protein Expression in Mice

“…Following previous optimizations, all samples were tested undiluted in a blind fashion. Luminex 100 (Luminex Corporation, Austin, TX, USA) was used for the immunoassay and Luminex 100 IS software to analyze the bead median fluorescence intensity, as in our recent study ( 28 ). All the tests were run in duplicate.…”

“…As in previous studies by our group ( 28 , 29 ), total RNA was prepared using the TRI Reagent (Molecular Research Center, Inc., Cincinnati, OH, USA) and Direct-Zol™ RNA isolation kit (Zymo Research, Irvine, CA, USA) following the manufacturer’s instructions. Then, the samples were treated with DNase I (Zymo Research, Irvine, CA, USA) to remove contaminating genomic DNA and quantified with a NanoDrop ND-2000 spectrophotometer (NanoDrop Technologies, Wilmington, DE, USA).…”