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

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. Here, we investigated its protective role against depression from the aspect of KYN metabolism in skeletal muscle. 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. 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. 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. © 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Citation

Lu Yan, Chu-Han Liu, Li Xu, Yi-Yun Qian, Ping-Ping Song, Min Wei, Bao-Lin Liu. Alpha-Asarone modulates kynurenine disposal in muscle and mediates resilience to stress-induced depression via PGC-1α induction. CNS neuroscience & therapeutics. 2023 Mar;29(3):941-956

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PMID: 36575869

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