Repeated Yueju, But Not Fluoxetine, Induced Sustained Antidepressant Activity in a Mouse Model of Chronic Learned Helplessness: Involvement of CaMKII Signaling in the Hippocampus

Zhilu Zou; Jiaru Huang; Qingqing Yang; Yuxuan Zhang; Bo Xu; Ping Wang; Gang Chen

doi:10.1155/2022/1442578

Repeated Yueju, But Not Fluoxetine, Induced Sustained Antidepressant Activity in a Mouse Model of Chronic Learned Helplessness: Involvement of CaMKII Signaling in the Hippocampus

Evid Based Complement Alternat Med. 2022 Feb 24:2022:1442578. doi: 10.1155/2022/1442578. eCollection 2022.

Authors

Zhilu Zou^{1

2

3

4}, Jiaru Huang², Qingqing Yang⁵, Yuxuan Zhang⁵, Bo Xu¹, Ping Wang¹, Gang Chen^{2

3

4}

Affiliations

¹ School of Basic Medicine, Hubei University of Chinese Medicine, Wuhan 430065, China.
² Interdisciplinary Institute for Personalized Medicine in Brain Disorders, Jinan University, Guangzhou 510632, China.
³ Departments of Psychiatry & Clinical and Translational Institute of Psychiatric Disorders, First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
⁴ Co-innovation Center of Neurodegeneration, Nantong University, Nantong 226001, China.
⁵ Center for Translational Systems Biology and Neuroscience, Key Laboratory of Integrative Biomedicine for Brain Diseases, Nanjing University of Chinese Medicine, Nanjing 210023, China.

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.