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Involvement of PI3K/AKT Pathway in the Rapid Antidepressant Effects of Crocetin in Mice with Depression-Like Phenotypes

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Abstract

The current first-line antidepressants have the drawback of slow onset, which greatly affects the treatment of depression. Crocetin, one of the main active ingredients in saffron (Crocus sativus L.), has been demonstrated to have antidepressant activities, but whether it has a rapid antidepressant effect remains unclear. This study aimed to investigate the onset, duration, and mechanisms of the rapid antidepressant activity of crocetin (20, 40 and 80 mg/kg, intraperitoneal injection) in male mice subjected to chronic restraint stress (CRS). The results of behavioral tests showed that crocetin exerted rapid antidepressant-like effect in mice with depression-like phenotypes, including rapid normalization of depressive-like behaviors within 3 h, and the effects could be maintained for 2 days. Hematoxylin-eosin (HE) and Nissl staining showed that crocetin ameliorated hippocampal neuroinflammation and nerve injuries in mice with depression-like phenotypes. The levels of inflammatory factors, corticosterone and pro brain-derived neurotrophic factor in crocetin-administrated mice serum were significantly reduced compared with those in the CRS group, as well as the levels of inflammatory factors in hippocampus. What’s more, Western blot analyses showed that, compared to CRS-induced mice, the relative levels of mitogen-activated kinase phosphatase 1 and toll-like receptor 4 were significantly reduced after the administration of crocetin, and the relative expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP-response element binding protein, phosphorylated phosphoinositide 3 kinase (p-PI3K)/PI3K, phosphorylated protein kinase B (p-AKT)/AKT, phosphorylated glycogen synthase kinase 3β (p-GSK3β)/GSK3β, phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR were markedly upregulated. In conclusion, crocetin exerted rapid antidepressant effects via suppressing the expression of inflammatory cytokines and the apoptosis of neuronal cells through PI3K/AKT signaling pathways. The rapid antidepressant effect of crocetin (40 mg/kg) could be maintained for at least 2 days after single treatment.

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Data will be made available on request.

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Funding

This study was financially supported by the “Leading Goose” R&D Program of Zhejiang (No. 2022C03050), the China National Key R&D Program (No. 2017YFE0130100), the Science and Technology Planning Project of Jinhua (NO. 2020-1-025), the Jiaxing Key Discipiline of Medicine-Clinical Pharmacy (No. 2023-ZC-008) and the Science and Technology Planning Project of Quzhou (NO. 2021K23).

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  1. Susu Lin and Ziwei Chen have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, 314001, People’s Republic of China

    Susu Lin & Wenyu Sun

  2. College of Pharmaceutical Sciences, Zhejiang University of Technology, No. 18 Chaowang Road, Hangzhou, 310014, People’s Republic of China

    Susu Lin, Ziwei Chen, Fei Fei, Zijin Xu & Ping Wang

  3. School of Biomedical engineering, Southern Medical University, Guangzhou, 510515, People’s Republic of China

    Zhaoruncheng Wu

  4. College of Pharmacy, Jiangxi Medical College, Shangrao, 334000, Jiangxi, People’s Republic of China

    Zijin Xu

  5. Institute of Natural Medicine and Health Product, School of Advanced Study, Taizhou University, Taizhou, 318000, People’s Republic of China

    Yingpeng Tong

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Contributions

PW and WS conceived and designed the experiments; SL and ZC performed the experiments; ZW, and FF analyzed and interpreted the data; ZX and YT contributed reagents and analysis tools; SL and ZC wrote the paper. All authors reviewed the manuscript.

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Correspondence to Wenyu Sun or Ping Wang.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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The animal experiment part of this project was approved by the animal ethics committee of Zhejiang University of Technology with approval number 20190603064, and experiment was conducted as per the Guide for the Care and Use of Laboratory Animals at the Zhejiang University of Technology, Hangzhou, China.

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Lin, S., Chen, Z., Wu, Z. et al. Involvement of PI3K/AKT Pathway in the Rapid Antidepressant Effects of Crocetin in Mice with Depression-Like Phenotypes. Neurochem Res 49, 477–491 (2024). https://doi.org/10.1007/s11064-023-04051-2

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