N-palmitoyl-D-glucosamine, A Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice

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.

Systematic analysis of critical genes and pathways identified a signature of neuropathic pain after spinal cord injury

“…Furthermore, TLRs are key receptors in various acute and chronic diseases, which can activate the inflammatory cascade and manifest by amplifying the inflammatory response (Iannotta et al, 2021). Reports have shown that SCI has a significant inducing effect on the TLR signalling pathway and induces pro‐inflammatory signals, such as NF‐κB, STAT signalling and lipopolysaccharide signalling (Morrison et al, 2021).…”

lncRNA MEG3 aggravated neuropathic pain and astrocyte overaction through mediating miR-130a-5p/CXCL12/CXCR4 axis

“…The toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) axis is activated following CCI-induced NP [ 52 ]. It is often recognized as a vital pathway in charge of inflammatory cytokines expression and release [ 53 ].…”

PEA-OXA Mitigates Oxaliplatin-Induced Painful Neuropathy through NF-κB/Nrf-2 Axis

“…Numerous studies have been directed to identify molecules with the capacity to relieve the symptoms of OIPN; on this basis, different endogenous lipid mediators have been identified as capable of reducing the inflammatory processes caused by OIPN [18]. PEA plays an important role among the lipid mediators in neuropathic pain [10,19,20], as well as in controlling of inflammatory phenomena and oxidative stress [7,21]. Recently, it was found that the pharmacological inhibition of the enzyme NAAA produces a marked analgesic and anti-inflammatory effect [9,22]; therefore, treatment with PEA-OXA associates the known effects of PEA with those of NAAA inhibition, which has, among other effects, an increase in endogenous endocannabinoid levels.…”