Neuroactive steroids induce changes in fetal sheep behavior during normoxic and asphyxic states

Allopregnanolone and related steroids are potent γ-aminobutyric acid receptor-A receptor agonistic allosteric modulators that suppress central nervous system (CNS) activity; in some species, these neurosteroids regulate normal CNS activity before birth. The aims of this study were to determine the effect of suppressing allopregnanolone production on behavioral responses to transient asphyxia in late gestation fetal sheep using the 5α-reductase (R)-2 inhibitor, finasteride. Specificity of the effects of finasteride was assessed by co-infusion of alfaxalone, a synthetic analog of allopregnanolone. Fetal catheters and electrodes for measurement of the electrocorticogram (ECoG) and nuchal electromyogram were implanted at 125 days of gestation, and an inflatable occluder was placed to allow umbilical cord occlusion (UCO). At of gestation, fetuses received carotid arterial infusion of vehicle (2-hydroxypropyl-β-cyclodextrin; 40% w/vol), finasteride (40 mg/kg/h), alfaxalone (5 mg/kg/h), or finasteride+alfaxalone. A further three groups of fetuses were subjected to 5 min UCO at 30 min after the start of each infusion regime. Finasteride treatment alone increased the incidence of arousal-like activity; this was reduced by co-infusion of alfaxalone. After UCO, finasteride treatment caused a prolongation of sub-low voltage (LV) ECoG activity and increase in aberrant ECoG spike activity when compared to vehicle-treated UCO fetuses. After UCO, alfaxalone treatment reduced the incidence of sub-LV, reduced the number of aberrant EEG spikes, and restored ECoG activity to the pattern observed after UCO in vehicle-treated fetuses. These results confirm that neurosteroids significantly modulate normal CNS activity in the late gestation fetus, modify, and limit the effects of asphyxia on the brain.

[1]  D. Walker,et al.  Role of neurosteroids in regulating cell death and proliferation in the late gestation fetal brain , 2009, Neuroscience.

[2]  D. Walker,et al.  Inhibition of neurosteroid synthesis increases asphyxia-induced brain injury in the late gestation fetal sheep , 2007, Neuroscience.

[3]  Yehezkel Ben-Ari,et al.  Effects of seizures on developmental processes in the immature brain , 2006, The Lancet Neurology.

[4]  J. Reynolds,et al.  Chronic Prenatal Ethanol Exposure Increases Glucocorticoid‐Induced Glutamate Release in the Hippocampus of the Near‐Term Foetal Guinea Pig , 2006, Journal of neuroendocrinology.

[5]  D. Walker,et al.  Hypoxia Potentiates Endotoxin-Induced Allopregnanolone Concentrations in the Newborn Brain , 2006, Neonatology.

[6]  A. Gunn,et al.  Suppression of post-hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep , 2006, Neuropharmacology.

[7]  C. Frye,et al.  Attenuating 5α-pregnane-3α-ol-20-one formation in the hippocampus of female rats increases pentylenetetrazole-induced seizures , 2005, Epilepsy & Behavior.

[8]  E. Yan,et al.  Increased allopregnanolone levels in the fetal sheep brain following umbilical cord occlusion , 2004, The Journal of physiology.

[9]  D. Walker,et al.  Lipid Peroxidation, Caspase-3 Immunoreactivity, and Pyknosis in Late-Gestation Fetal Sheep Brain after Umbilical Cord Occlusion , 2004, Pediatric Research.

[10]  Jan G. Nijhuis,et al.  Fetal behavior , 2003, Neurobiology of Aging.

[11]  D. Walker,et al.  Changes in 5α-Pregnane Steroids and Neurosteroidogenic Enzyme Expression in the Perinatal Sheep , 2003, Pediatric Research.

[12]  D. Walker,et al.  Endotoxin Increases Sleep and Brain Allopregnanolone Concentrations in Newborn Lambs , 2002, Pediatric Research.

[13]  D. Walker,et al.  Effect of finasteride on behavioural arousal and somatosensory evoked potentials in fetal sheep , 2001, Neuroscience Letters.

[14]  M. Rogawski,et al.  Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy. , 2000, The Journal of pharmacology and experimental therapeutics.

[15]  M. Rogawski,et al.  Finasteride, a 5alpha-reductase inhibitor, blocks the anticonvulsant activity of progesterone in mice. , 1999, The Journal of pharmacology and experimental therapeutics.

[16]  D. Walker,et al.  Effects of pregnanolone on behavioural parameters and the responses to GABAA receptor antagonists in the late gestation fetal sheep , 1999, Neuropharmacology.

[17]  C. Frye,et al.  Seizure Activity Is Increased in Endocrine States Characterized by Decline in Endogenous Levels of the Neurosteroid 3α,5α-THP , 1998, Neuroendocrinology.

[18]  D. Walker,et al.  Effect of pregnane steroids on electrocortical activity and somatosensory evoked potentials in fetal sheep , 1998, Neuroscience Letters.

[19]  M. Serio,et al.  5α-Reductase Inhibitors, Chemical and Clinical Models , 1998, Steroids.

[20]  D. Ladle,et al.  Inhibition of brain 5α-reductase in pregnant rats: effects on enzymatic and behavioral activity , 1996, Brain Research.

[21]  Á. Meana,et al.  Interaction among alfaxalone, pregnenolone sulfate, and two GABAA agonists on hippocampal slices , 1996, Cellular and Molecular Neurobiology.

[22]  G. Biggio,et al.  Time-dependent changes in rat brain neuroactive steroid concentrations and GABAA receptor function after acute stress. , 1996, Neuroendocrinology.

[23]  W Wisden,et al.  The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  H. Szeto.  Behavioral states and their ontogeny: animal studies. , 1992, Seminars in perinatology.

[25]  M. Majewska,et al.  Neurosteroids: Endogenous bimodal modulators of the GABAA receptor mechanism of action and physiological significance , 1992, Progress in Neurobiology.

[26]  P. H. Moore,et al.  Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. Walker,et al.  Effect of feeding regimen on diurnal variation of breathing movements in late-gestation fetal sheep. , 1990, Journal of applied physiology.

[28]  I. McMillen,et al.  Effect of reduced uterine blood flow on fetal and maternal cortisol. , 1986, Journal of developmental physiology.

[29]  D. Walker,et al.  Changes in breathing, electrocortical and muscle activity in unanaesthetized fetal lambs with age. , 1983, The Journal of physiology.

[30]  R. Seamark,et al.  Progestagen metabolites in fetal sheep plasma: the effect of fetal nephrectomy. , 1979, Journal of developmental physiology.

[31]  M. Ballabio,et al.  Neuroactive steroids , 2007, Journal of Molecular Neuroscience.

[32]  C. Frye,et al.  Attenuating 5alpha-pregnane-3alpha-ol-20-one formation in the hippocampus of female rats increases pentylenetetrazole-induced seizures. , 2005, Epilepsy & Behavior.

[33]  M. Serio,et al.  5 alpha-reductase inhibitors, chemical and clinical models. , 1998, Steroids.

[34]  C. Frye,et al.  Seizure activity is increased in endocrine states characterized by decline in endogenous levels of the neurosteroid 3 alpha,5 alpha-THP. , 1998, Neuroendocrinology.

[35]  D. Walker,et al.  Suppression of arousal by progesterone in fetal sheep. , 1997, Reproduction, fertility, and development.

[36]  D. Ladle,et al.  Inhibition of brain 5 alpha-reductase in pregnant rats: effects on enzymatic and behavioral activity. , 1996, Brain Research.

[37]  P. Gluckman,et al.  Increased vulnerability to neuronal damage after umbilical cord occlusion in fetal sheep with advancing gestation. , 1994, American journal of obstetrics and gynecology.

[38]  G. Visser,et al.  The emergence of fetal behaviour. III. Individual differences and consistencies. , 1988, Early human development.