Abstract
Yueju pill is a traditional Chinese medicine formulated to treat syndromes of mood disorders. Here, we investigated the therapeutic effect of repeated low dose of Yueju in the animal model mimicking clinical long-term depression condition and the role of neural plasticity associated with PKA- (protein kinase A-) CREB (cAMP response element binding protein) and NMDA (N-methyl-D-aspartate) signaling. We showed that a single low dose of Yueju demonstrated antidepressant effects in tests of tail suspension, forced swim, and novelty-suppressed feeding. A chronic learned helplessness (LH) protocol resulted in a long-term depressive-like condition. Repeated administration of Yueju following chronic LH remarkably alleviated all of depressive-like symptoms measured, whereas conventional antidepressant fluoxetine only showed a minor improvement. In the hippocampus, Yueju and fluoxetine both normalized brain-derived neurotrophic factor (BDNF) and PKA level. Only Yueju, not fluoxetine, rescued the deficits in CREB signaling. The chronic LH upregulated the expression of NMDA receptor subunits NR1, NR2A, and NR2B, which were all attenuated by Yueju. Furthermore, intracerebraventricular administration of NMDA blunted the antidepressant effect of Yueju. These findings supported the antidepressant efficacy of repeated routine low dose of Yueju in a long-term depression model and the critical role of CREB and NMDA signaling.
Highlights
Major depressive disorder (MDD) is a state of low mood and aversion to activity that can affect a person’s thoughts, behavior, feelings, and sense of well-being [1]
A number of antidepressants, such as the first-line selective serotonin reuptake inhibitors (SSRIs), are available, a remarkable population of patients never attain sustained remission of their symptoms [4, 5]. These and other disadvantages such as delayed onset of efficacy of SSRIs challenge the traditional monoaminebased hypothesis of depression, and emerging evidence favors the neural plasticity hypothesis which proposes an important role of the impaired neural plasticity including neurotrophic factors, cAMP response element binding protein (CREB) signaling, synaptic plasticity influenced by N-methyl-D-aspartate (NMDA) signaling, adult neurogenesis in depression, and neural plasticity as the crucial targets for antidepressant action [6, 7]
The dose range from 1 g to 3 g/kg in mice was approximate to the routine use of Yueju nonprescriptively, and they were selected for testing antidepressant effect using TST, FST, and NSF
Summary
Major depressive disorder (MDD) is a state of low mood and aversion to activity that can affect a person’s thoughts, behavior, feelings, and sense of well-being [1]. A number of antidepressants, such as the first-line selective serotonin reuptake inhibitors (SSRIs), are available, a remarkable population of patients never attain sustained remission of their symptoms [4, 5] These and other disadvantages such as delayed onset of efficacy of SSRIs challenge the traditional monoaminebased hypothesis of depression, and emerging evidence favors the neural plasticity hypothesis which proposes an important role of the impaired neural plasticity including neurotrophic factors, cAMP response element binding protein (CREB) signaling, synaptic plasticity influenced by N-methyl-D-aspartate (NMDA) signaling, adult neurogenesis in depression, and neural plasticity as the crucial targets for antidepressant action [6, 7]. PKA-CREB and NMDA signaling, as well as BDNF was examined in the mice subjected to routine dose of Yueju following chronic learned helplessness procedure. The role of NMDA signaling in Yueju’s action was further verified by using intracerebroventricular pharmacological infusion approach
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