Neurosteroids in the brain neuron: Biosynthesis, action and medicinal impact on neurodegenerative disease

Kazuyoshi Tsutsui*, Synthia H. Mellon

*この研究の対応する著者

研究成果: Article査読

31 被引用数 (Scopus)

抄録

The brain has traditionally been considered to be a target site of peripheral steroid hormones. By contrast, new findings over the past decade have shown that the brain itself also has the capability of forming steroids de novo from cholesterol, the so-called "neurosteroids". To understand neurosteroid action in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed. Recently the Purkinje cell, a cerebellar neuron, has been identified as a major site for neurosteroid formation in the brain. Since this discovery, diverse actions of neurosteroids are becoming clear. The rat Purkinje cell actively synthesizes progesterone and 3α,5α-tetrahydroprogesterone (allopregnanolone) de novo from cholesterol during neonatal life, when cerebellar cortical formation occurs. Estrogen formation in this neuron may also occur in the neonate. Both progesterone and estradiol promote dendritic growth, spinogenesis and synaptogenesis via each cognate nuclear receptor in Purkinje neurons. We have used the Niemann-Pick type C (NP-C) mouse as a model for understanding neurosteroid action in the brain. NP-C is an autosomal recessive, childhood neurodegenerative disease characterized by defective intracellular cholesterol trafficking, resulting in Purkinje cell degeneration, as well as neuronal degeneration in other regions. Brains from adult NP-C mice contain less allopregnanolone than wild-type brain. Administration of allopregnanolone to neonatal NP-C mice increases Purkinje cell survival and delays neurodegeneration. Thus neurosteroid replacement therapy appears to be useful in ameliorating progression of the disease. Here we summarize the advances made in our understanding of the biosynthesis and actions of neurosteroids in the brain neuron. This review also describes medicinal impact of neurosteroids on neurodegenerative disease.

本文言語English
ページ(範囲)73-82
ページ数10
ジャーナルCentral Nervous System Agents in Medicinal Chemistry
6
1
DOI
出版ステータスPublished - 2006
外部発表はい

ASJC Scopus subject areas

  • 分子医療
  • 神経科学(全般)
  • 神経心理学および生理心理学

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