Alpha‐Asarone modulates kynurenine disposal in muscle and mediates resilience to stress‐induced depression via PGC‐1α induction

INTRODUCTION: Kynurenine (KYN) accumulation in periphery induces brain injury, responsible for depression. α‐Asarone is a simple phenylpropanoids that exerts beneficial effects on central nervous system. However, the effect of α‐asarone on periphery is unexplored. AIMS: Here, we investigated its protective role against depression from the aspect of KYN metabolism in skeletal muscle. METHODS: The antidepressant effects of α‐asarone were evaluated in chronic mild stress (CMS) and muscle‐specific PGC‐1α‐deficient mice. The effects of KYN metabolism were determined in mice and C2C12 myoblasts. RESULTS: α‐Asarone exerted antidepressant effects in CMS and KYN‐challenged mice via modulating KYN metabolism. In myoblasts, α‐asarone regulated PGC‐1α induction via cAMP/CREB signaling and upregulated KYN aminotransferases (KATs) to increase KYN clearance in a manner dependent on PGC‐1α. KAT function is coupled with malate–aspartate shuttle (MAS), while α‐asarone combated oxidative stress to protect MAS and mitochondrial integrity by raising the NAD(+)/NADH ratio, ensuring effective KYN disposal. In support, the antidepressant effect of α‐asarone was diminished by muscle‐specific PGC‐1α deficient mice subjected to KYN challenge. CONCLUSION: KATs coupled with MAS to clear KYN in muscle. α‐Asarone increased PGC‐1α induction and promoted KYN disposal in muscle, suggesting that protection of mitochondria is a way for pharmacological intervention to depression.