1. N-palmitoyl-D-glucosamine, a Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice.
- Author
-
Iannotta M, Belardo C, Trotta MC, Iannotti FA, Vitale RM, Maisto R, Boccella S, Infantino R, Ricciardi F, Mirto BF, Ferraraccio F, Panarese I, Amodeo P, Tunisi L, Cristino L, D'Amico M, Di Marzo V, Luongo L, Maione S, and Guida F
- Subjects
- Analgesics pharmacology, Animals, Anti-Inflammatory Agents pharmacology, Calcium Signaling drug effects, Cytokines metabolism, Drug Evaluation, Preclinical, Glycolipids pharmacology, HEK293 Cells, Humans, Hyperalgesia etiology, Keratitis chemically induced, Keratitis pathology, Lipopolysaccharides toxicity, Lymphocyte Antigen 96 metabolism, Male, Mice, MicroRNAs genetics, Models, Molecular, Nociceptors drug effects, Nociceptors physiology, Protein Conformation, RAW 264.7 Cells, Random Allocation, Sciatic Nerve injuries, TRPA1 Cation Channel metabolism, Analgesics therapeutic use, Anti-Inflammatory Agents therapeutic use, Glycolipids therapeutic use, Hyperalgesia prevention & control, Keratitis drug therapy, Neuralgia drug therapy, Toll-Like Receptor 4 antagonists & inhibitors
- Abstract
Toll-like receptors (TLRs) are key receptors through which infectious and non-infectious challenges act with consequent activation of the inflammatory cascade that plays a critical function in various acute and chronic diseases, behaving as amplification and chronicization factors of the inflammatory response. Previous studies have shown that synthetic analogues of lipid A based on glucosamine with few chains of unsaturated and saturated fatty acids, bind MD-2 and inhibit TLR4 receptors. These synthetic compounds showed antagonistic activity against TLR4 activation in vitro by LPS, but little or no activity in vivo. This study aimed to show the potential use of N -palmitoyl-D-glucosamine (PGA), a bacterial molecule with structural similarity to the lipid A component of LPS, which could be useful for preventing LPS-induced tissue damage or even peripheral neuropathies. Molecular docking and molecular dynamics simulations showed that PGA stably binds MD-2 with a MD-2/(PGA)3 stoichiometry. Treatment with PGA resulted in the following effects: (i) it prevented the NF-kB activation in LPS stimulated RAW264.7 cells; (ii) it decreased LPS-induced keratitis and corneal pro-inflammatory cytokines, whilst increasing anti-inflammatory cytokines; (iii) it normalized LPS-induced miR-20a-5p and miR-106a-5p upregulation and increased miR-27a-3p levels in the inflamed corneas; (iv) it decreased allodynia in peripheral neuropathy induced by oxaliplatin or formalin, but not following spared nerve injury of the sciatic nerve (SNI); (v) it prevented the formalin- or oxaliplatin-induced myelino-axonal degeneration of sciatic nerve. SIGNIFICANCE STATEMENT We report that PGA acts as a TLR4 antagonist and this may be the basis of its potent anti-inflammatory activity. Being unique because of its potency and stability, as compared to other similar congeners, PGA can represent a tool for the optimization of new TLR4 modulating drugs directed against the cytokine storm and the chronization of inflammation., Competing Interests: The authors declare no conflict of interest.
- Published
- 2021
- Full Text
- View/download PDF