Safety and efficacy of a new micronized formulation of the ALIAmide palmitoylglucosamine in preclinical models of inflammation and osteoarthritis pain.

Abstract

BACKGROUND:

Osteoarthritis is increasingly recognized as the result of a complex interplay between inflammation, chrondrodegeneration, and pain. Joint mast cells are considered to play a key role in orchestrating this detrimental triad. ALIAmides down-modulate mast cells and more generally hyperactive cells. Here we investigated the safety and effectiveness of the ALIAmide N-palmitoyl-D-glucosamine (PGA) in inflammation and osteoarthritis pain.

METHODS:

Acute toxicity of micronized PGA (m-PGA) was assessed in rats following OECD Guideline No.425. PGA and m-PGA (30 mg/kg and 100 mg/kg) were orally administered to carrageenan (CAR)-injected rats. Dexamethasone 0.1 mg/kg was used as reference. Paw edema and thermal hyperalgesia were measured up to 6 h post-injection, when also myeloperoxidase activity and histological inflammation score were assessed. Rats subjected to intra-articular injection of sodium monoiodoacetate (MIA) were treated three times per week for 21 days with PGA or m-PGA (30 mg/kg). Mechanical allodynia and motor function were evaluated at different post-injection time points. Joint histological and radiographic damage was scored, articular mast cells were counted, and macrophages were immunohistochemically investigated. Levels of TNF-α, IL-1β, NGF, and MMP-1, MMP-3, and MMP-9 were measured in serum using commercial colorimetric ELISA kits. One- or two-way ANOVA followed by a Bonferroni post hoc test for multiple comparisons was used.

RESULTS:

Acute oral toxicity of m-PGA resulted in LD50 values in excess of 2000 mg/kg. A single oral administration of PGA and m-PGA significantly reduced CAR-induced inflammatory signs (edema, inflammatory infiltrate, and hyperalgesia), and m-PGA also reduced the histological score. Micronized PGA resulted in a superior activity to PGA on MIA-induced mechanical allodynia, locomotor disability, and histologic and radiographic damage. The MIA-induced increase in mast cell count and serum level of the investigated markers was also counteracted by PGA and to a significantly greater extent by m-PGA.

CONCLUSIONS:

The results of the present study showed that PGA is endorsed with anti-inflammatory, pain-relieving, and joint-protective effects. Moreover, it proved that particle size reduction greatly enhances the activity of PGA, particularly on joint pain and disability. Given these results, m-PGA could be considered a valuable option in the management of osteoarthritis.

• Authors: Marika Cordaro, Rosalba Siracusa, Daniela Impellizzeri, Ramona D' Amico, Alessio Filippo Peritore, Rosalia Crupi, Enrico Gugliandolo, Roberta Fusco, Rosanna Di Paola, Carlo Schievano, Salvatore Cuzzocrea
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 21 Issue 1 Pg. 254 (11 28 2019) ISSN: 1478-6362 [Electronic] England
• PMID: 31779692 (Publication Type: Journal Article)

Chemical References

• Analgesics
• Tumor Necrosis Factor-alpha
• Carrageenan
• Matrix Metalloproteinase 1
• Glucosamine
• Iodoacetic Acid

Topics

• Analgesics (chemistry, pharmacology)
• Animals
• Carrageenan
• Female
• Glucosamine (chemistry, pharmacology)
• Hyperalgesia (chemically induced, prevention & control)
• Inflammation (drug therapy, physiopathology)
• Iodoacetic Acid
• Male
• Mast Cells (cytology, drug effects)
• Matrix Metalloproteinase 1 (blood)
• Osteoarthritis (drug therapy, physiopathology)
• Pain (chemically induced, physiopathology, prevention & control)
• Pain Measurement (methods)
• Particle Size
• Rats, Sprague-Dawley
• Toxicity Tests
• Tumor Necrosis Factor-alpha (blood)