The effect of the electrophilic fatty acid nitro-oleic acid on TRP channel function in sensory neurons

Abstract

Nitro-oleic acid (NO-OA) and related nitroalkenes are electrophilic fatty acid derivatives that are present in normal tissues at nanomolar concentrations and can increase significantly during inflammation. These substances can suppress multiple intracellular signaling pathways contributing to inflammation by reversible Michael addition reactions with nucleophilic residues such as cysteine and histidine leading to post-translational modification of proteins. NO-OA also can influence inflammation and pain by acting on transient receptor potential (TRP) channels in primary sensory neurons. TRPV1, TRPA1 and TRPC can respond to electrophilic fatty acids because they have ankyrin-like repeats in their N terminus that are rich in cysteine residues that react with electrophiles and other thiol modifying species. NO-OA acts on TRP channels to initially depolarize and induce firing in sensory neurons followed by desensitization and suppression of firing. In vivo experiments revealed that pretreatment with NO-OA reduces nociceptive behavior evoked by local administration of a TRPA1 agonist (AITC) to the rat hind paw. These results raise the possibility that NO-OA might be useful clinically to reduce neurogenic inflammation and certain types of painful sensations by desensitizing TRPA1 expressing nociceptive afferents.

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19

“…Repeated doses induce desensitization [ 173 ]. The electrophilic fatty acid NO 2 -OA acts on TRP channels to initially depolarize and induce firing in sensory neurons followed by desensitization and suppression of firing [ 174 ]. NO 2 -OA attenuates intracellular oxidative stress through Nrf2 and suppression of NADPH oxidase [ 175 ].…”

Pharmacokinetic and Pharmacodynamic Effects of OralCXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

“…10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10) is a specific regioisomer of OA‐NO 2 , characterized by a nitro group on carbon 10 with effects similar to the mixed isomer. NFAs, in general, and CXA‐10, in particular, demonstrate potential as effective therapeutic agents in multiple disease indications in which metabolic and oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles …”

Nitroxidative stress in pain and opioid-induced adverse effects: therapeutic opportunities

“…157 TRPC channels were found to interact with NOX, 148,156,171 and their stimulation leads to NO formation and increased excitability in endothelial cells. 130 Moreover, nitrated fatty acids can activate TRPC channels on nociceptive sensory neurons 15 ; thus, possible effects of nitroxidative stress on these receptors also in pain settings warrant further investigation. Toll-like receptors (TLRs) are other crucial players in the neuroimmune crosstalk leading to neuronal excitability.…”