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Loureirin C and Xanthoceraside Prevent Abnormal Behaviors Associated with Downregulation of Brain Derived Neurotrophic Factor and AKT/mTOR/CREB Signaling in the Prefrontal Cortex Induced by Chronic Corticosterone Exposure in Mice

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Abstract

Brain derived neurotrophic factor (BDNF) is one of the most abundant neurotrophic factors, and its deficits are involved in the pathogenesis of major depressive disorders (MDD). Loureirin C (Lou C) is a compound derived from red resin extracted from the stems of Chinese dragon's blood. Xanthoceraside (Xan) is a triterpenoid saponin extracted from the husks of Xanthoceras sorbifolia Bunge. These compounds have neuroprotective effects through upregulation of BDNF. The present study aimed to evaluate whether Lou C and Xan attenuate abnormal behaviors induced by chronic corticosterone (CORT) administration. CORT was administered subcutaneously to mice for 3 weeks, and Lou C and Xan, dispensed orally once a day during the last 2 weeks of CORT administration. Chronic CORT administration induced abnormal behaviors such as prolonged starting latency in the open field test, decreased social interaction time in the social interaction test and prolonged latency to eat in the novelty suppressed feeding test. Chronic CORT administration decreased the expression levels of BDNF and the phosphorylation of protein kinase B (Akt), mammalian target of rapamycin (mTOR), and the cAMP response element binding protein (CREB) in the prefrontal cortex. Lou C and Xan dose-dependently prevented the abnormal behaviors and decreased the expression levels of BDNF and in phosphorylation of AKT, mTOR, and CREB in the prefrontal cortex of CORT mice. These results suggest that Lou C and Xan could be attractive candidates for pharmacotherapy of MDD at least in part, given their propensity to increase BDNF expression and phosphorylation of AKT, mTOR, and CREB.

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Abbreviations

BDNF:

Brain derived neurotrophic factor

CORT:

Corticosterone

Lou C:

Loureirin C

MDD:

Major depressive disorders

ERK:

Extracellular signal-regulated kinase

Akt:

Protein kinase B

mTOR:

Mammalian target of rapamycin

CREB:

CAMP response element binding protein

TrkB:

Tropomyosin related kinase B

7,8-DHF:

7,8-Dihydroxyflavone

HPA:

Hypothalamic–pituitary–adrenal

PI3K:

Phosphatidylinositol 3-kinase

PFC:

Prefrontal cortex

NAc:

Nucleus accumbens

HIP:

Hippocampus

Xan:

Xanthoceraside

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Acknowledgements

We thank our lab members for helpful discussions. We would like to thank Editage (www.editage.com) for English language editing.

Funding

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (17H04252, 20K07931, and 20K16679), by the Private University Research Branding Project from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT), and by Japan Science and Technology Agency (JST) FOREST Program (JPMJFR215H). This work was supported by a grant from the Education and Research Facility of Animal Models for Human Diseases at Fujita Health University, by a research grant from the Smoking Research Foundation, and by the Takeda Science Foundation.

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  1. Yang Yang and Akihiro Mouri have contributed equally to this work.

Authors and Affiliations

  1. Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Fujita Health University, Graduate School of Health Sciences, Toyoake, Aichi, 470-1192, Japan

    Yang Yang, Akihiro Mouri, Qiaohui Lu, Kazuo Kunisawa, Hisayoshi Kubota, Masaya Hasegawa & Mami Hirakawa

  2. Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China

    Yang Yang, Qiaohui Lu & Zou Libo

  3. Department of Advanced Diagnostic System Development, Fujita Health University, Graduate School of Health Sciences, Toyoake, Aichi, 470-1192, Japan

    Yuko Mori & Kuniaki Saito

  4. Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Toyoake, Aichi, 470-1192, Japan

    Toshitaka Nabeshima

  5. Japanese Drug Organization of Appropriate Use and Research, Toyoake, Aichi, 468-0069, Japan

    Akihiro Mouri, Kuniaki Saito & Toshitaka Nabeshima

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Contributions

YY, QL and AM devised the project and the main conceptual ideas, conducted the experiments, and wrote the manuscript. KK, HK, MH, MH, and YM assisted with the experiments. KS and ZL contributed to the discussion section in the manuscript. TN and AM supervised the study and finalized the manuscript.

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Correspondence to Akihiro Mouri.

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Yang, Y., Mouri, A., Lu, Q. et al. Loureirin C and Xanthoceraside Prevent Abnormal Behaviors Associated with Downregulation of Brain Derived Neurotrophic Factor and AKT/mTOR/CREB Signaling in the Prefrontal Cortex Induced by Chronic Corticosterone Exposure in Mice. Neurochem Res 47, 2865–2879 (2022). https://doi.org/10.1007/s11064-022-03694-x

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