Mechanisms underlying the antidepressant-like effects of intranasal administration of resolvins in animal models of depression and treatment-resistant depression
Project/Area Number |
19K07120
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 47040:Pharmacology-related
|
Research Institution | Kanazawa University |
Principal Investigator |
|
Project Period (FY) |
2019-04-01 – 2022-03-31
|
Project Status |
Completed (Fiscal Year 2021)
|
Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
Keywords | レゾルビン / ω-3不飽和脂肪酸 / 抗うつ薬 / うつ病 / 治療抵抗性うつ病 / 内側前頭前野 / mTORC1 / ω-3系不飽和脂肪酸 |
Outline of Research at the Start |
現在病院で処方されている抗うつ薬は、即効性がなく、効果が得られるまでに数週間以上の服用が必要であり、約3割の患者には効果がないため、新たな抗うつ薬の創出が求められている。私たちは、体内でDHAやEPAを原料にして生成されるレゾルビン類という物質に着目し、これまでにレゾルビン類を脳内に直接投与すると即効性の抗うつ効果が得られることを明らかにしてきた。本研究では、レゾルビン類の臨床応用を見据え、これらの点鼻薬が、既存の抗うつ薬が効かないうつ病にも有効か否かを調べるとともに、その作用メカニズムを明らかにすることを目的とする。
|
Outline of Final Research Achievements |
In this study, we found that intranasal (i.n.) administration of resolvin E1 (RvE1), a bioactive lipid mediator derived from EPA, produces antidepressant-like effects via BDNF/VEGF release and the subsequent activation of mTORC1 in the medial prefrontal cortex (mPFC) in mouse models of depression, including a treatment-resistant depression model. We also found that intraperitoneal and oral administration of o-BZ-RvE2, a metabolically stable analog of resolvin E2, an EPA metabolite, produces antidepressant-like effects via mTORC1 activation in the mPFC. These findings suggest that i.n. administration is a viable and promising route for the delivery of unstable resolvins to the brain and can pave the way for the application of resolvins in the treatment of depression. Moreover, this study suggests that stable resolvin analogs could be lead compounds for novel antidepressants.
|
Academic Significance and Societal Importance of the Research Achievements |
うつ病の患者数は世界で約2.8億人と言われ、深刻な社会的・経済的損失をもたらしている。一方、既存の抗うつ薬は効果発現が遅く、3割の患者が治療抵抗性を示すため、新たな抗うつ薬の開発が喫緊の課題である。本研究の成果により、レゾルビン類やその誘導体が新たな抗うつ薬候補化合物として有望であることが示唆された。
|
Report
(4 results)
Research Products
(67 results)
-
-
-
-
-
-
-
-
-
-
-
-
-
[Journal Article] Acute restraint stress augments the rewarding memory of cocaine through activation of α1 adrenoceptors in the medial prefrontal cortex of mice.2020
Author(s)
Wada, S., Yanagida, J., Sasase, H., Zhang, T., Li, X., Kamii, H., Domoto, M., Deyama, S., Hinoi, E., Yamanaka, A., Nishitani, N., Nagayasu, K., Kaneko, S., Minami, M., Kaneda, K.
-
Journal Title
Neuropharmacology
Volume: 166
Pages: 107968-107968
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
-
-
-
[Journal Article] Role of neuronal VEGF signaling in the prefrontal cortex in the rapid antidepressant effects of ketamine2019
Author(s)
Deyama S, Bang E, Wohleb ES, Li XY, Kato T, Gerhard DM, Dutheil S, Dwyer JM, Taylor SR, Picciotto MR, Duman RS.
-
Journal Title
American Journal of Psychiatry
Volume: 176
Issue: 5
Pages: 388-400
DOI
Related Report
Peer Reviewed / Int'l Joint Research
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-