Trace charactethation of neurosteroids to develop a new antipsychotic agent targeting neurosteroidogenesis
| Project/Area Number |
18590031
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Physical pharmacy
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| Research Institution | Kanazawa University |
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Principal Investigator |
HIGASHI Tatsuya Kanazawa University, Graduate School of Natural Science and Technology, Associate Professor (90272963)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,080,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2007: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Neurosteroid / LC-MS / Derivatization / Stress / Rat brain / Antipsychotic agent / 神経活性アンドロゲン / コルチコイド / 検出指向誘導体化 / GABA_A受容体 / 抗不安・鎮静作用 / エタノール |
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| Research Abstract |
Neurosteroids bind to the γ-aminobutyric acid type A (GABA_A) receptors with a high affinity, positively modulate the action of GABA at these receptors and thus elicit marked anesthetic, sedative and anxiolytic effects. The quantitative analysis of the endogenous neurosteroids in the brain and serum is very important for characterization of their physiological functions and the mechanism by which they affect the brain functions. The brain and serum assays of the neurosteroids can also contribute to the development of new antipsychotic agents targeting neurosteroidogenesis. Based on this background information, sensitive liquid chromatography-tandem mass spectrometric methods that enable the quantification of trace neurosteroids (5α-redduced pregnane neurosteroids, 3-oxo-4-ene-neurosteroids, neuroavtive androgens and tetrahydrocorticosterone isomers) in rat brain and serum were developed and validated. Some methods employed derivatization procedures, which were very effective in increas
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ing the detection responses of steroids.
New discoveries from the animal studies using the developed methods were as follows. 1) The brain allopregnanolone, epiallopregnanolone and 5α-dihydroprogesterone levels are rapidly elevated by immobilization stress and ethanol administration. Epiallopregnanolone is the brain-specific product. 2) The stress-induced level changes in the brain testosterone and androstenedione (androstane steroids) are much lower than those of progesterone and its metabolites (pregnane steroids). 3) Most of the brain testosterone is derived from the peripheral organs, while a fair amount of 5α-dihydrotestosterone is continuously synthesized in the brain. The GABAergic neuroactive androgen, 5α-androstane-3α,17β-diol, is always present in the male rat brain and its level is not influenced by the stress. 4) 3α,5α-Tetrahydrocorticosterone is present in the brain of both male and female rats after being subjected to the immobilization stress, but there is a sex difference in its brain level. Less
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Report
(3 results)
Research Products
(44 results)
