Neuroinflammation-Modulating Properties Combining Glutathione, N-Acetylcysteine, and Uridine Monophosphate in a Formulation Supplement: An In Vitro Study

Background: Neuropathic pain is a complex condition often resistant to current therapies due to limited efficacy and adverse effects. Nutraceuticals offer promising alternatives, combining antioxidant and anti-inflammatory properties with good tolerability. This study aimed to compare the effects of a commercial nutraceutical formulation, SUPERALA CARNITINE^® (Pharma Suisse Laboratories SpA, Milan, Italy), containing Alpha-Lipoic Acid (ALA), with a novel formulation, called SUPERALA CARNITINE^® Forte, where ALA and vitamin B6 were replaced by N-acetylcysteine (NAC), Glutathione (GSH), and Uridine monophosphate (UMP). Methods: An indirect gut-peripheral nerve axis was employed to simulate oral absorption, metabolism, and effect on nervous tissues using 3D in vitro models. Both formulations and their individual components were assessed for cytotoxicity and permeability in the gut model (Caco-2 cells in Transwell^®) and, after gut metabolism, for antioxidant capacity, anti-inflammatory activity, and neuroprotective potential in the peripheral nerve model. Results: SUPERALA CARNITINE^® Forte improved cell viability and favoured the maintenance of intestinal integrity, showing enhanced permeability, and significantly reduced oxidative stress (OS) and pro-inflammatory cytokines (TNF-α, IL-2) at the peripheral nervous system. In addition, it increased levels of neuronal markers (p75, MPZ, NRG1, ERβ) and decreased NaV1.7 and NaV1.8 activity, indicating greater neuroprotection and analgesic modulation than the ALA-based formula. Conclusions: The replacement of ALA and vitamin B6 with NAC, GSH, and UMP produced favorable responses in vitro on neuronal cells, supporting a hypothetical potential interest in this nutraceutical combination and justifying further future in vivo investigations.