Caffeine Ameliorates Stress-induced Depression By Promoting PGC-1α Expression In Skeletal Muscle

Caffeine is an alkaloid structurally identified as 1,3,7-trimethylxanthien. The most common plants in which caffeine exists are coffee,tea,and so on. Coffee and tea are the most consumed beverages worldwide, so caffeine has become a part of people’s life. Through the meta-analysis, researchers found a protective effect of caffeine on risk of depression. Depression is a heterogeneous disorder, defined as losing desires, slower mind, losing appetite and easily agitate. Severe depression lead to suicide, which has become a serious social and medical problem, and the exact neuronal mechanism causing the disease are yet to be discovered. Some researches showed that caffeine has antidepressant activity, but the mechanism underlying is not clearly. In this study,we subjected the C57BL/6J male mice to a chronic mild stress(CMS) protocol. This protocol involves multiple,daily, mild stressors at unpredictable time validated to induce depressive behavior. After 8 weeks of CMS, the mice displayed depressive behavior as shown by increased immobility time in tail suspension test(TST)and forced swim tests(FST)(measures of despair with good predictive value for antidepressant effects), compared with nonstressed control animals. Strikingly, these CMS effects were completely absent in the mice of caffeine group. Caffeine has no effect on locomotor activity or sucrose consumption test.Caffeine did not protect mice against all the effects of CMS and the mice showed decreases in body weight gain.The modulation of glutamate transmission and plasticity by stress-induced neuroinflammatory pathways may constitute a link between depression and chronic stress. In particular, the kynurenine pathway of tryptophan degradation is activated by stress. Levels of kynurenine(KYN) and its metabolites 3-hydroxykynurenine(3HK)and kynurenic acid(KYNA) in patients are strongly correlated to depression. We used C2C12 cell strains as a model to study the effect of caffeine on the metabolism of KYN. The results showed that caffeine promotes the expression of kynurenien aminotransferases1(KAT1), which could enhance the conversion of kynurenine into kynurenic acid,a metabolite unable to cross the blood-brain barrier(BBB). PGC-1α atranscription factor is the upstream of KATs, which was activated by caffeine in C2C12 cells.In the animal experiments, we also discovered that caffeine promoted the expression of KAT1, KAT3 and KAT4 in the mouse’s muscle tissue. Through the RT-PCR test, we found that the mRNA expression of PGC-1ɑ is elevated by caffeine.At last, we analyzed the level of KYN and KYNA in plasma, and it turned out that the level of KYN was lower in the caffeine group, while the level of KYNA is not different.This study demonstrated that caffeine had antidepressant effects. The mechanism may be attributed to kynurenine pathway of tryptophan degradation being activated by caffeine in the mouse’s muscle tissue.