Neurosteroids and Neuroprotection

Stress in Pregnancy Activates Neurosteroid Production in the Fetal Brain
Jonathan J. Hirst^a, Tamara Yawno^b, Phuong Nguyen^c, David W. Walker<sup>b

a</sup>School of Biomedical Sciences, University of Newcastle, Callaghan,
^bDepartment of Physiology, Monash University, Clayton, and
^cNational Trauma Research Institute, The Alfred Hospital, Prahran, Australia

Address of Corresponding Author

Neuroendocrinology 2006;84:264-274 (DOI: 10.1159/000097990)

  Key Words

• Pregnane steroids
• Allopregnanolone
• Progesterone
• Placental steroidogenesis
• Fetus
• Neuroprotection
• Placenta

  Abstract

Neurosteroids such as allopregnanolone are potent agonists at the GABA_A receptor and suppress the fetal CNS activity. These steroids are synthesized in the fetal brain either from cholesterol or from circulating precursors derived from the placenta. The concentrations of allopregnanolone are remarkably high in the fetal brain and rise further in response to acute hypoxic stress, induced by constriction of the umbilical cord. This response may result from the increased 5-reductase and cytochrome P-450_SCC expression in the brain. These observations suggest that the rise in neurosteroid concentrations in response to acute hypoxia may represent an endogenous protective mechanism that reduces excitotoxicity following hypoxic stress in the developing brain. In contrast to acute stress, chronic hypoxemia induces neurosteroidogenic enzyme expression without an increase in neurosteroid concentrations and, therefore, may pose a greater risk to the fetus. At birth, the allopregnanolone concentrations in the brain fall markedly, probably due to the loss of placental precursors; however, stressors, including hypoxia and endotoxin-induced inflammation, raise allopregnanolone concentrations in the newborn brain. This may protect the newborn brain from hypoxia-induced damage. However, the rise in allopregnanolone concentrations was also associated with increased sleep. This rise in sedative steroid levels may depress arousal and contribute to the risk of sudden infant death syndrome. Our recent findings indicate that acute hypoxic stress in pregnancy initiates a neurosteroid response that may protect the fetal brain from hypoxia-induced cell death, whereas the decline in allopregnanolone levels after birth may result in greater vulnerability to brain injury in neonates.

Copyright © 2006 S. Karger AG, Basel

  Author Contacts

Jonathan J. Hirst
School of Biomedical Sciences
University of Newcastle
Callaghan, NSW 2308 (Australia)
Tel. +61 2 4921 7965, Fax +61 2 4921 7903, E-Mail Jon.Hirst@newcastle.edu.au

  Article Information

Presented at the Sixth International Congress of Neuroendocrinology, June 19-22, 2006, Pittsburgh, Pa., USA.

Received: October 16, 2006
Accepted: October 17, 2006
Published online: December 11, 2006
Number of Print Pages : 11
Number of Figures : 3, Number of Tables : 1, Number of References : 68