L-Acetylcarnitine causes analgesia in mice modeling Fabry disease by up-regulating type-2 metabotropic glutamate receptors

Abstract

Fabry disease (FD) is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3). A hallmark symptom of FD patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. Previous studies have shown that Acetyl-L-carnitine (ALC) has neuroprotective, neurotrophic, and analgesic activity in animal models of neuropathic pain. To study the action of ALC on neuropathic pain associated with FD, we treated α-GalA gene null mice (α-GalA(-/0)) with ALC for 30 days. In α-Gal KO mice ALC treatment induced acute and long-lasting analgesia, which persisted 1 month after drug withdrawal. This effect was antagonized by single administration of LY341495, an orthosteric antagonist of mGlu2/3 metabotropic glutamate receptors. We also found an up-regulation of mGlu2 receptors in cultured DRG neurons isolated from 30-day ALC treated α-GalA KO mice. However, the up-regulation of mGlu2 receptors was no longer present in DRG neurons isolated 30 days after the end of treatment. Taken together, these findings suggest that ALC induces analgesia in an animal model of FD by up-regulating mGlu2 receptors, and that analgesia is maintained by additional mechanisms after ALC withdrawal. ALC might represent a valuable pharmacological strategy to reduce pain in FD patients.

Effect of L. Plantarum Y279 and W. Cibaria Y113 on microorganism, lipid oxidation and fatty acid metabolites in Yu jiaosuan, A Chinese tradition fermented snack

“…As fermentation progressed, 3-Dehydroxycarnitine, l -Acetylcarnitine, 11(R)-HETE, 2-Hydroxystearic acid, 15-KETE and Ricinoleic acid gradually accumulated and were more highly expressed in the inoculated fermentation group. Studies have indicated that l -Acetylcarnitine has neuroprotective, neurotrophic and analgesic activity ( Formaggio, Rimondini, Delprete et al, 2022 ). By contrast, (R)-3-Hydroxy-tetradecanoic acid, 6,15-Diketo,13,14-dihydro-PGF1a, 8,9-DiHETrE, Stearic acid, 2,3-dinor-6-oxoprostaglandin F1alpha, Prostaglandin A1, 16-Hydroxy-10-oxohexadecanoic acid, Hexadecanedioic acid, (9S,10S)-10-hydroxy-9-(phosphonooxy)octadecanoate, and Troxilin B3 accumulated gradually in the natural fermentation group.…”

Anti-Hyperalgesic Efficacy of Acetyl L-Carnitine (ALCAR) Against Visceral Pain Induced by Colitis: Involvement of Glia in the Enteric and Central Nervous System

“…In particular, the up-regulation of mGlu2R mediated by ALCAR takes a few days to become established but lasts for several weeks after treatment interruption [44,45]. In a recent study, ALCAR was found to induce analgesia in mice modelling Fabry disease [46], an X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme which leads to multisystemic clinical manifestations, among them neuropathic pain and gastrointestinal dysfunctions that appears in the early stage of the disease [47,48]. The authors demonstrated that the ALCAR analgesic effect was mediated by an up-regulation of mGlu2Rs in cultured DRG neurons isolated from 30-day ALCAR-treated α-GalA KO mice.…”

“…The authors demonstrated that the ALCAR analgesic effect was mediated by an up-regulation of mGlu2Rs in cultured DRG neurons isolated from 30-day ALCAR-treated α-GalA KO mice. Anyway, since the up-regulation of mGlu2 receptors was no longer present in DRG neurons isolated 30 days after the end of treatment, despite the persistence of analgesia, the authors concluded that ALCAR long-lasting analgesia was maintained by additional mechanisms [46]. Indeed, several mechanisms are probably involved in the effects of ALCAR on pain, one among all the regulation of M1 muscarinic receptor activity in the central cholinergic system [11,21].…”