Antidepressant-Like Effects and Cognitive Enhancement of Coadministration of Chaihu Shugan San and Fluoxetine: Dependent on the BDNF-ERK-CREB Signaling Pathway in the Hippocampus and Frontal Cortex

Abstract

Background. Fluoxetine (FLU) is the first-line and widely used medication for depression; however, FLU treatment is almost ineffective in 30%-40% of patients with depression. In addition, there are some problems in FLU treatment, such as delayed efficacy, large side effects, and poor tolerance. Chaihu Shugan San (CSS) is a classic and effective antidepressant Chinese herbal medicine that has been used in China for thousands of years. CSS or coadministration of CSS and FLU has become one of the most recommended methods in the treatment of depression in China. However, the specific pathways of CSS and coadministration of CSS and FLU for antidepressant are still unclear. Objective. This study was designed to evaluate the antidepressant effects of CSS and coadministration of CSS and FLU. Methods. The chronic unpredictable mild stress (CUMS) rat model was used to simulate depression. 120 healthy adult male Sprague-Dawley (SD) rats were randomly divided into seven groups: the control group, CUMS group, low-dose CSS group, high-dose CSS group, FLU group, coadministration of low-dose CSS and FLU group, and coadministration of high-dose CSS and FLU group. The rats in different groups were given different interventions. Then, the depression-like behavior and cognitive function were evaluated by the sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), and Y-maze test. What is more, the antidepressant mechanism of CSS and coadministration of CSS and FLU were studied through BDNF mRNA, ERK mRNA, CREB mRNA, BDNF, p-ERK/ERK, and p-CREB/CREB levels in the hippocampus and frontal cortex by Western blot and RT-PCR. Results. Compared with the CUMS group, CSS and coadministration of CSS and FLU could alleviate the depressive symptoms and improve cognitive function in CUMS rats (p<0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (p<0.05). Besides, the high-dose CSS combined with the fluoxetine group was significantly better than the fluoxetine group and CSS group (p<0.05). Discussion and Conclusion. Finally, we found that both CSS and coadministration of CSS and FLU play an antidepressant role, which may be due to the regulation of the BDNF/ERK/CREB signaling pathway in the hippocampus and frontal cortex. Among them, the coadministration of CSS and FLU can enhance the antidepressant effect of CSS or FLU alone, and the underlying mechanism needs further investigation.

Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish (Danio rerio)

“…In our experiment, the Tukey’s test did not reveal any difference in the mRNA levels of Creb , Bdnf , Ntrk2a, and Ngfra genes in zebrafish treated with fluoxetine and fluoxetine together with pCPA compared with the control ones. These results agree with data obtained earlier on rodents [ 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ] and zebrafish [ 48 ] and indicate that the BDNF system in zebrafish is resistant to prolonged fluoxetine treatment.…”

Neuroprotective Effect of Carotenoid-Rich Enteromorpha prolifera Extract via TrkB/Akt Pathway against Oxidative Stress in Hippocampal Neuronal Cells

“…The ERK/TrkB/CREB pathway is another mechanism underlying neuronal cell survival [ 33 , 34 ]. As shown in Figure 4 , EAEP completely enhanced the expression of BDNF as well as p-ERK, p-CREB, and p-TrkB ( Figure 4 A).…”

Neuroprotective Activity of Polyphenol-Rich Ribes diacanthum Pall against Oxidative Stress in Glutamate-Stimulated HT-22 Cells and a Scopolamine-Induced Amnesia Animal Model

“…The activation of both the Akt/Nrf2/antioxidant response element (ARE) signaling pathway and the ERK/BDNF/TrkB pathway was reported to be related to neuroprotective effects [ 10 , 22 ]. Hence, we supposed that the pathways could be activated by RDP treatment because RDP protected neuronal cells against oxidative stress-induced cell death.…”

“…BDNF exerts its biological function through binding to its receptor, tyrosine receptor kinase B (TrkB), which initiates multiple signaling cascades [ 10 , 11 , 12 , 19 , 20 ]. The cAMP-calcium response element-binding protein (CREB), which a transcription factor, is phosphorylated and activated by BDNF, mediating the indispensable transcription of genes for the survival and differentiation of neurons, [ 21 , 22 ]. Mature BDNF activates tyrosine receptor kinase B (TrkB) signaling, and then TrkB activates the downstream effectors, including protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) [ 10 , 21 ].…”