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.