Central Nervous System Agents in Medicinal Chemistry

(Formerly Current Medicinal Chemistry - Central Nervous System Agents)

Back

Neurosteroids in the Brain Neuron: Biosynthesis, Action and Medicinal Impact on Neurodegenerative Disease

Author(s): Kazuyoshi Tsutsui, Synthia H. Mellon.

Abstract:

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.

Keywords: Neurosteroids, progesterone, allopregnanolone, neuronal growth, synaptogenesis, neurodegeneration, Purkinje neuron, Niemann-Pick type C disease

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

VOLUME: 6
ISSUE: 1
Year: 2006
Page: [73 - 82]
Pages: 10
DOI: 10.2174/187152406776056555