Neural Plasticity Associated with Hippocampal PKA-CREB and NMDA Signaling Is Involved in the Antidepressant Effect of Repeated Low Dose of Yueju Pill on Chronic Mouse Model of Learned Helplessness

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.

Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice

“…Therefore, in this study, we explored the underlying mechanism of the stimulatory effect of MEM on tau phosphorylation by examining the expression of different NMDARs. Our results showed that CRS caused an increase in the levels of NMDARs containing GluN2A and GluN2B, which is in accordance with the previous studies [86], while MEM treatment suppressed the expression of both the GluN2A and GluN2B NMDAR subunits after 16-day CRS. In contrast, treatment with 5 mg/kg MEM did not suppress GluN2B upregulation following 28-day CRS and treatment with 10 mg/kg MEM even induced the upregulation of GluN2B expression compared to that in CRS-only mice.…”

Immediate and persistent antidepressant-like effects of Chaihu-jia-Longgu-Muli-tang are associated with instantly up-regulated BDNF in the hippocampus of mice

“…It is, however, worth noting that the dose of CLM to induce rapid and lasting antidepressant effects was only half of the clinical dose. In contrast, higher than clinical dose was required for Yueju pill to elicit rapid antidepressant-like effects [19], whereas we found a single full clinical dose of Yueju only induced a shorter duration of antidepressant activity [27]. Importantly, we determined experimentally an optimal dose of CLM for rapid antidepressant-like response, which is consistent with the two half doses of prescription of the herb preparation for daily use in humans.…”

Beneficial Effects of Crocin against Depression via Pituitary Adenylate Cyclase-Activating Polypeptide

“…Further, crocin significantly increases the expression of p-CREB, brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) in the rat hippocampus [ 13 ]. Our previous research showed that Yueju pills [ 14 ] and gardenia [ 15 ] have antidepressant effects, with gardenia yellow pigment (GYP, a collection of compounds with shared structure of crocin) being one of the constituents responsible for their antidepressant efficacy [ 16 ]. Transcriptomic analyses detected a unique upregulation of hippocampal PACAP expression post Yueju (unpublished).…”