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

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.