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Biomolecules2026; 16(8); 1142; doi: 10.3390/biom16081142

Neosaxitoxin Downregulates Inflammation in an Equine In Vivo Model of Osteoarthritis.

Abstract: Chronic synovial inflammation is a hallmark of osteoarthritis progression and is tightly regulated by synovial macrophages. Recently, voltage-gated sodium channels (NaV) have emerged as potent modulators of macrophage-driven inflammation, positioning them as novel therapeutic targets. Among selective NaV channel blockers, neosaxitoxin exerts remarkable anesthetic and immunomodulatory effects; however, its effects on joint inflammation upon intra-articular delivery remain unexplored. Using an equine model of bilateral carpal osteoarthritis, this study evaluated the immunomodulatory and tissue-preserving effects of intra-articular neosaxitoxin. Sixteen horses were randomized into two experimental groups (n = 8/each): Neosaxitoxin in one joint and triamcinolone (+control) in the contralateral joint; or neosaxitoxin in one joint and saline (-control) in the contralateral joint. Clinical parameters, synovial fluid cytology and cytokine profiles, and histological changes in synovium and cartilage were assessed over 30 days. Neosaxitoxin reduced synovial inflammation, evidenced by decreased synovial effusion and surface temperature, along with improved joint flexion. Furthermore, synovial fluid from neosaxitoxin-treated joints exhibited lower counts of erythrocytes, neutrophils, total protein, and key pro-inflammatory mediators (IL-1β and IL-6) compared to saline-treated controls. Histologically, neosaxitoxin-treated joints exhibited modest synovial inflammatory cell infiltration and minor cartilage abnormalities. In contrast, control joints exhibited synovial hyperplasia, fibrovascular proliferation, and cartilage degeneration. Our data suggests that intra-articular neosaxitoxin better preserved joint homeostasis by limiting synovial inflammation and cartilage damage. These results warrant further investigation on Neosaxitoxin as a candidate treatment for inflammatory arthropathies.
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Publication Date: 2026-08-06 PubMed ID: 42650808PubMed Central: PMC13511278DOI: 10.3390/biom16081142Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

Overview

  • This study investigates the effects of neosaxitoxin, a selective sodium channel blocker, on joint inflammation and tissue preservation in an equine model of osteoarthritis.
  • Researchers compared neosaxitoxin to standard treatments and controls, demonstrating that neosaxitoxin reduces inflammation and limits joint damage in osteoarthritis.

Background

  • Osteoarthritis (OA) is characterized by chronic inflammation of the synovial membrane (synovitis), which plays a critical role in disease progression.
  • Synovial macrophages regulate inflammation and have become targets for new OA therapies.
  • Voltage-gated sodium channels (NaV), which are involved in electrical signaling in cells, have been identified as significant modulators of macrophage-driven inflammation.
  • Neosaxitoxin is a selective NaV channel blocker known for its anesthetic and immunomodulatory properties but its effect on joint inflammation after direct injection into joints had not been previously studied.

Study Design and Methods

  • Sixteen horses with surgically induced bilateral carpal osteoarthritis were used to model OA in vivo in a controlled way.
  • The horses were divided into two experimental groups of 8 each:
    • Group 1: Neosaxitoxin injected into one joint and triamcinolone (a corticosteroid) into the contralateral joint to compare neosaxitoxin with a standard anti-inflammatory treatment.
    • Group 2: Neosaxitoxin injected into one joint and saline (placebo control) into the contralateral joint to evaluate neosaxitoxin against no treatment beyond injection.
  • Assessment period lasted 30 days, during which the following were measured:
    • Clinical parameters such as joint effusion (fluid accumulation), surface temperature, and joint flexibility.
    • Synovial fluid analysis including cell counts (erythrocytes and neutrophils), protein concentration, and inflammatory cytokines including interleukins IL-1β and IL-6.
    • Histological examination of synovium and cartilage to detect inflammation, cell infiltration, tissue proliferation, and cartilage degeneration.

Key Findings

  • Neosaxitoxin significantly reduced synovial inflammation as shown by:
    • Lower synovial effusion and decreased surface temperature of treated joints compared to saline controls.
    • Improved joint flexion, indicating better mobility and less pain or stiffness.
  • Synovial fluid analyses from neosaxitoxin-treated joints showed:
    • Reduced counts of red blood cells (erythrocytes) and neutrophils, which are indicators of inflammation and tissue damage.
    • Lower total protein concentration, suggesting a reduction in inflammatory exudate.
    • Decreased levels of pro-inflammatory cytokines IL-1β and IL-6, both of which are key drivers of osteoarthritic joint inflammation and degradation.
  • Histopathology revealed that neosaxitoxin-treated joints had:
    • Only mild infiltration of inflammatory cells in the synovium.
    • Minor abnormalities in cartilage structure, indicating tissue protection.
  • The control joints (especially saline-treated) showed:
    • More pronounced synovial hyperplasia (thickening of the synovial lining) and fibrovascular proliferation, both signs of active inflammation and repair response.
    • More severe cartilage degeneration, consistent with progressive osteoarthritis.

Conclusions and Implications

  • Intra-articular administration of neosaxitoxin in horses with osteoarthritis reduced synovial inflammation and helped preserve cartilage integrity better than saline and comparably to triamcinolone.
  • The findings highlight neosaxitoxin’s potential as a novel therapeutic agent targeting NaV channels to modulate macrophage-driven inflammation within joints.
  • Neosaxitoxin’s dual anesthetic and immunomodulatory properties may offer a distinct advantage in managing OA-related inflammation and pain.
  • Further research, including clinical trials in humans or other models, is needed to validate these results and to explore the safety, dosing, and long-term efficacy of neosaxitoxin in inflammatory arthropathies.

Cite This Article

APA
Dörner C, Lagos N, Oyaneder L, González C, Ramírez-Toloza G, Menarim BC. (2026). Neosaxitoxin Downregulates Inflammation in an Equine In Vivo Model of Osteoarthritis. Biomolecules, 16(8), 1142. https://doi.org/10.3390/biom16081142

Publication

Biomolecules
ISSN: 2218-273X
NlmUniqueID: 101596414
Country: Switzerland
Language: English
Volume: 16
Issue: 8
PII: 1142

Researcher Affiliations

Dörner, Cristóbal
  • Escuela de Medicina Veterinaria, Sede Viña del Mar, Facultad de Ciencias de la Vida, Universidad Andres Bello, Quillota 980, Viña del Mar 2520000, Chile.
  • Programa de Doctorado en Ciencias Silvoagropecuarias y Veterinarias, Campus Sur, Universidad de Chile, Santa Rosa 11315, Santiago 8820808, Chile.
Lagos, Néstor
  • Membrane Biochemistry Laboratory, Department of Physiology and Biophysics, Faculty of Medicine, University of Chile, Independencia 1027, Santiago 8380000, Chile.
Oyaneder, Lissette
  • Equestria Equine Medical Center, Quillota 2260000, Chile.
González, Carlos
  • Escuela de Medicina Veterinaria, Sede Santiago, Facultad de Ciencias de la Vida, Universidad Andres Bello, República 440, Santiago 8320000, Chile.
Ramírez-Toloza, Galia
  • Department of Animal Preventive Medicine, Faculty of Veterinary Medicine, University of Chile, Santa Rosa 11735, Santiago 6640022, Chile.
Menarim, Bruno C
  • Gluck Equine Research Center, Department of Veterinary Sciences, Martin-Gatton College of Agriculture, Food and Environment, University of Kentucky, Lexington, KY 40546, USA.

MeSH Terms

  • Animals
  • Osteoarthritis / drug therapy
  • Osteoarthritis / pathology
  • Osteoarthritis / metabolism
  • Horses
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Saxitoxin / analogs & derivatives
  • Saxitoxin / pharmacology
  • Saxitoxin / administration & dosage
  • Saxitoxin / therapeutic use
  • Disease Models, Animal
  • Synovial Fluid / drug effects
  • Synovial Fluid / metabolism
  • Synovial Membrane / drug effects
  • Synovial Membrane / pathology
  • Cytokines / metabolism
  • Male

Grant Funding

  • 21230257/2023 / Agencia Nacional de Investigación y Desarrollo

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

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