Abstract
Objective Depression is characterized with long disease length, whereas one major disadvantage of current mainstream treatment of depression is a high rate of relapse and recurrence. A sustained antidepressant activity is proposed to facilitate the prevention of relapse/recurrence. Here we compared the long-term antidepressant effect of Yueju, a traditional Chinese medicine formula, and a conventional antidepressant, fluoxetine, as well as revealing the underlying mechanism of long-term antidepressant effect of Yueju. Methods Clinical long-term depression condition was modelled by using chronic learned helplessness (cLH) protocol in ICR strain mice. The short-term and long-term antidepressant effects of drugs were assessed with learned helplessness (LH), tail suspension test (TST), forced swim test (FST), and novelty-suppressed feeding (NSF) test. The expression of PKA, CaMKII signaling, and NR1, the NMDA receptor subunit, in hippocampus was determined. A CaMKII inhibitor (KN-62) was used to assess the role of CaMKII signaling in antidepressant effects of Yueju or fluoxetine. Results In the mice exposed to chronic learned helplessness (cLH) procedure, administration of Yueju or fluoxetine for 3 weeks elicited comparable antidepressant effects, indicated by learned helplessness test, as well as TST and NSF. However, 5 days after termination of the 3-week-long drug administration, only mice previously treated with Yueju still showed the alleviation of depressive-like behaviors. At this time, the downregulation of PKA and p-CaMKII/CaMKII and upregulation of NMDA receptor subunit NR1 in the hippocampus were normalized in animals previously treated with Yueju. In contrast, none of the expressions of these proteins were changed in mice previously treated with fluoxetine. Interestingly, an administration of KN-62 blunted the antidepressant effect of Yueju. Conclusion These findings showed the sustained antidepressant efficacy of chronic treatment with routine dose of Yueju and the CaMKII signaling activation may play a critical role in the sustained antidepressant response.
Highlights
Depression is a common psychiatric disorder characterized by persistent and significant low mood and a high suicidal tendency in severe cases [1]. It is a disease with high incidence, high disability rate, and high recurrence rate [2]. e episode of depression lasts for at least 2 weeks, and a substantial proportion of its burden arises through relapses and chronic courses: more than half of those with a first episode of depression go on to have a second one, and the Evidence-Based Complementary and Alternative Medicine majority of them have more episodes [3, 4]
We identified the major compounds of Yueju pills by using high performance liquid chromatography (HPLC), in which 11 compounds were identified, including chlorogenic acid, geniposide, ferulic acid, senkyunolide I, senkyunolide A, n-butylphthalide, ligustilide, 3-butylidenephthalide, and atractylodin, and the structures of major compounds are shown in Supplementary Figure S2
Two-week treatment with low dose of Yueju improved the deficiency in PKA/CREB/BDNF and decreased expressions of NMDA receptor subunits in the hippocampus in a chronic learned helplessness paradigm, whereas repeated fluoxetine only reversed some but not all of these signaling deficits, in parallel with the more depressive symptoms alleviated by Yueju than by fluoxetine [19]. us, more comprehensive and persistent improvement in the molecular deficits may account for the better antidepressant effects
Summary
Depression is characterized with long disease length, whereas one major disadvantage of current mainstream treatment of depression is a high rate of relapse and recurrence. A CaMKII inhibitor (KN-62) was used to assess the role of CaMKII signaling in antidepressant effects of Yueju or fluoxetine. In the mice exposed to chronic learned helplessness (cLH) procedure, administration of Yueju or fluoxetine for 3 weeks elicited comparable antidepressant effects, indicated by learned helplessness test, as well as TST and NSF. 5 days after termination of the 3-week-long drug administration, only mice previously treated with Yueju still showed the alleviation of depressive-like behaviors. At this time, the downregulation of PKA and p-CaMKII/CaMKII and upregulation of NMDA receptor subunit NR1 in the hippocampus were normalized in animals previously treated with Yueju. Conclusion. ese findings showed the sustained antidepressant efficacy of chronic treatment with routine dose of Yueju and the CaMKII signaling activation may play a critical role in the sustained antidepressant response
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Evidence-based complementary and alternative medicine : eCAM
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
