Venlafaxine alleviates complete Freund's adjuvant-induced arthritis in rats: Modulation of STAT-3/IL-17/RANKL axis

Life Sci. 2019 Jun 1:226:68-76. doi: 10.1016/j.lfs.2019.03.063. Epub 2019 Mar 28.

Abstract

Aims: Rheumatoid arthritis is usually accompanied by various comorbidities especially on the psychological side such as depression. This study aimed at revealing the potential curative effects of venlafaxine (VFX), a serotonin/norepinephrine reuptake inhibitor (SNRI), on experimentally-induced arthritis in rats.

Methods: Arthritis was induced by injecting complete Freund's adjuvant (CFA, 0.1 ml, s.c.). One day thereafter, VFX (50 mg/kg, p.o.) was given for 21 days. Methotrexate was used as a standard disease modifying anti-rheumatic drug.

Key findings: CFA injection caused prominent arthritis evident by the increase in the hind paw and ankle diameter accompanied by elevating tumor necrosis factor-alpha, interleukin-6, interleukin-17 and matrix metalloproteinase-3 levels, effects that were diminished by VFX. Moreover, VFX down regulated gene expressions of receptor activator of nuclear factor kappa-B (NF-кB) ligand and signal transducer and activator of transcription-3 beside hampering immunohistochemical expression of vascular endothelial growth factor and NF-кB. This SNRI also improved the oxidant status of the hind limb as compared to the arthritic group. Nonetheless, MTX was better in amendment of arthritis authenticated by its effect on some inflammatory and oxidative stress biomarkers.

Significance: This study provides a novel therapeutic use of VFX as a considerable anti-arthritic drug and offers an incentive to expand its use in RA.

Keywords: Arthritis; Complete Freund's adjuvant; Inflammation; Methotrexate; Venlafaxine.

MeSH terms

  • Animals
  • Antirheumatic Agents
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / metabolism
  • Arthritis, Rheumatoid
  • Biomarkers
  • Disease Models, Animal
  • Freund's Adjuvant / pharmacology
  • Interleukin-17 / metabolism
  • Interleukin-6
  • Male
  • Matrix Metalloproteinase 3
  • Methotrexate / pharmacology
  • NF-kappa B / drug effects
  • Oxidative Stress
  • RANK Ligand / drug effects
  • RANK Ligand / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • STAT3 Transcription Factor / drug effects
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha
  • Venlafaxine Hydrochloride / metabolism*
  • Venlafaxine Hydrochloride / pharmacology*

Substances

  • Antirheumatic Agents
  • Biomarkers
  • Il17a protein, rat
  • Interleukin-17
  • Interleukin-6
  • NF-kappa B
  • RANK Ligand
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Tumor Necrosis Factor-alpha
  • Venlafaxine Hydrochloride
  • Freund's Adjuvant
  • Matrix Metalloproteinase 3
  • Methotrexate