Phoenixin-14 Modulates Nrf2/HO-1, NF-κB, and Apoptotic Pathways in a Rat Model of Monosodium Glutamate-Induced Neurotoxicity.

Abstract

Monosodium glutamate (MSG) induces neuronal injury through oxidative stress, inflammation, and apoptosis, contributing to the pathogenesis of neurodegenerative disorders. Phoenixin-14 (PNX-14), a recently identified neuropeptide, exhibits strong antioxidant, anti-inflammatory, and anti-apoptotic properties. This study investigated the potential protective effects of PNX-14 against MSG-induced neurotoxicity in rats. Adult male Wistar rats were assigned to four groups: control, PNX-14 (5 nmol/kg/day for 3 days), MSG (4 g/kg/day for 7 days), and MSG + PNX-14. Blood and brain tissues were collected after treatment. Serum total antioxidant status (TAS) and total oxidant status (TOS) were measured. Gene expression levels of antioxidative (Nrf2, HO-1), inflammatory (NF-κB, IL-1β), apoptotic (caspase-3, Bax, Bcl-2), and related targets (PNX-14, Gpr173) were assessed using qRT-PCR. Histopathological alterations were examined by hematoxylin-eosin staining, while Nrf2, HO-1, and caspase-3 protein expressions were evaluated immunohistochemically. MSG markedly reduced TAS and elevated TOS, while PNX-14 reversed this imbalance by improving antioxidant status. MSG also upregulated NF-κB, IL-1β, Bax, and caspase-3 while suppressing Nrf2, HO-1, and Bcl-2 expression. Conversely, PNX-14 administration enhanced antioxidant defenses, downregulated NF-κB and IL-1β signaling, and modulated apoptosis by increasing Bcl-2 and decreasing Bax and caspase-3 levels. Histopathological evaluations supported these findings, showing reduced neuronal degeneration in PNX-14-treated groups. In conclusion, PNX-14 provides substantial neuroprotection against MSG-induced toxicity by restoring TAS and TOS balance, strengthening antioxidant defense, suppressing neuroinflammation, and regulating apoptotic pathways. These results indicate that PNX-14 may be an appropriate therapies option for neurodegenerative disorders associated with glutamate.