αCGRP Activates PI3K/Akt to Exert Antioxidant Effects and Improve the Survival Rate and Functional Status of Cortical Neurons.

We are now entering a transformative era in aging research, which offers unprecedented opportunities to extend healthy lifespan. Based on recent scientific advances, it may be possible to prevent, delay, or even reverse certain age-related diseases. This study investigates the antioxidant and anti-aging effects of αCGRP (Calca) in the rat cerebral cortex. Calca knockout (Calca-KO) rats and their wild-type littermates were treated with D-galactose (D-gal) to induce an oxidative aging model, and αCGRP was administered via tail vein injection as a rescue intervention. Cortical tissues were subjected to RNA sequencing (RNA-seq) for pathway analysis, and lipid metabolites were analyzed both qualitatively and quantitatively using UPLC-MS/MS. The results showed that Calca-/- D-gal-treated rats exhibited a significant decrease in platform crossings and prolonged escape latency, along with increased total swimming distance and swimming speed. Notably, αCGRP treatment significantly improved these behavioral deficits. This was accompanied by reduced expression of apoptosis-related genes (β-catenin, Bcl-2, and NRF2) and activation of the PI3K/Akt signaling pathway, promoting antioxidant responses and cellular survival. Metabolomic analysis revealed that oxidized linoleic acid metabolites, including 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE) and their derivatives (9- and 13-oxoODE), were significantly elevated in the Calca-/- D-gal group and were markedly reduced following αCGRP treatment. Collectively, these findings indicate that αCGRP exerts antioxidant effects by activating the PI3K/Akt pathway, thereby reducing neuronal apoptosis and improving the survival and functional integrity of cortical neurons. Overall, αCGRP confers neuroprotection under oxidative stress conditions.