Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives

Abstract

Within the lipidome oxidized phospholipids (OxPL) form a class of chemically highly reactive metabolites. OxPL are acutely produced in inflamed tissue and act as endogenous, proalgesic (pain-inducing) metabolites. They excite sensory, nociceptive neurons by activating transient receptor potential ion channels, specifically TRPA1 and TRPV1. Under inflammatory conditions, OxPL-mediated receptor potentials even potentiate the action potential firing rate of nociceptors. Targeting OxPL with D-4F, an apolipoprotein A-I mimetic peptide or antibodies like E06, specifically binding oxidized headgroups of phospholipids, can be used to control acute, inflammatory pain syndromes, at least in rodents. With a focus on proalgesic specificities of OxPL, this article discusses, how targeting defined substances of the epilipidome can contribute to mechanism-based therapies against primary and secondary chronic inflammatory or possibly also neuropathic pain.

Transcriptomic Profiling in Mice With CB1 receptor Deletion in Primary Sensory Neurons Suggests New Analgesic Targets for Neuropathic Pain

“…Notably, in the early phase of CB1cKO, the functional pathways of DEGs are mainly enriched in material metabolism, energy balance, and complement and coagulation cascades. Besides these pathways, we also found the following genes changed, such as Alb ( Vincenzetti et al, 2019 ), Apoa1 ( Bellei et al, 2017 ; Oehler et al, 2020a ; Oehler et al, 2020b ), Nnat ( Chen et al, 2010 ), Vgf ( Rizzi et al, 2008 ; Fairbanks et al, 2014 ), and Sting1 ( Donnelly et al, 2021 ), which may be associated with hyperalgesia in the early phase of CB1 knockdown. Interestingly, most DEGs involved in material metabolism and energy balance in the early phase of CB1cKO returned to normal after 2 weeks (the late phase of CB1cKO), including major urinary protein family and serine (or cysteine) peptidase inhibitor family.…”

Oxidized phospholipids on alkyl-amide scaffold demonstrate anti-endotoxin and endothelial barrier-protective properties

“…Synthesis of alkyl-amide-OxPCs was performed in 2 stages. First, lysoamino-PC (6) was synthesized. This stage consisted of 6 individual reactions, three of which were performed in one pot (Fig.…”

“…Accumulation of OxPLs has been described in a number of pathological conditions [1][2][3][4]. Recent advances in analysis of OxPLs as disease biomarkers in combination with animal disease model data support the notion that OxPLs play causative pathogenic role in a number of disease states [5][6][7][8][9]. More detailed understanding of the biological role of OxPLs and mechanisms of their action is hampered by the lack of synthetic individual molecular species.…”

Differences in plasma lipoprotein profiles between patients with chronic peripheral neuropathic pain and healthy controls: an exploratory pilot study

“… 1 , 39 Apart from cytokine-related regulatory actions in the immune system, cytokines also induce several modifications in both lipid composition and lipoprotein metabolism during inflammation. 26 Notably, lipoproteins are mostly known for their involvement in the development of atherosclerosis and cardiovascular disease (CVD); however, oxidized lipoproteins and lipids have recently been implicated in nociception, 32 , 35 thereby linking lipoproteins, lipid dysfunction, inflammatory, and nociceptive mechanisms.…”

“… 26 , 41 This chronification of inflammatory responses seems to be an underlying mechanism in the onset and development of several disease states including CVD, atherosclerosis, diabetes, rheumatoid arthritis, as well as in chronification of pain. 32 , 41 …”