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      Brain Allopregnanolone in the Fetal and Postnatal Rat in Response to Uteroplacental Insufficiency

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          Background/Aims: Allopregnanolone suppresses central nervous system activity and has neuroprotective actions in hypoxia-induced brain injury. In pregnant sheep allopregnanolone concentrations are high during fetal life and decline rapidly after birth. We investigated brain allopregnanolone concentrations of fetal and postnatal rats derived from normal and growth restricted pregnancies. Methods: Bilateral uterine vessel ligation (or sham) was performed at gestation day 18 to induce uteroplacental insufficiency in WKY rats (n = 7–8 per group). Brain allopregnanolone was measured by radioimmunoassay at 2 study ages, gestation day 20 (n = 6 per group) and postnatal day 6 (n = 6–8 per group), from control and growth-restricted pups. Results: Fetal brain allopregnanolone concentrations were higher in growth-restricted fetuses compared to control (p < 0.05). Allopregnanolone concentrations decreased at birth with a greater decline in growth restriction (p < 0.05). Postnatal day 6 brain allopregnanolone concentrations were lower in growth restriction (p < 0.05). Conclusions: Growth restriction is a potent stimulus for neurosteroid synthesis in the fetal brain in late pregnancy. The low concentrations of allopregnanolone in the growth-restricted postnatal brain suggest a delay in the capacity of the adrenal gland or brain to synthesize pregnane steroids or their precursors and may render the postnatal brain vulnerable to hypoxia-induced injury.

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          Most cited references 19

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          Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain.

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            Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery.

            The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of gamma-aminobutyric acid type A (GABAA) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36Cl- uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for gamma2L GABAA receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also alpha1, alpha2, alpha3, alpha4, beta1, beta2, beta3, and gamma2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5alpha-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36Cl- uptake and the decrease of gamma2L mRNA observed during pregnancy. These results indicate that the plasticity of GABAA receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.
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              Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.

              Uteroplacental insufficiency in the rat restricts fetal growth, impairs mammary development, compromising postnatal growth; and increases adult BP. The roles of prenatal and postnatal nutritional restraint on later BP and nephron endowment in offspring from mothers that underwent bilateral uterine vessel ligation (restricted) on day 18 of pregnancy were examined. Sham surgery (control) and a group of rats with reduced litter size (reduced; litter size reduced at birth to five, equivalent to restricted group) were used as controls. Offspring (control, reduced, and restricted) were cross-fostered on postnatal day 1 onto a control (normal lactation) or restricted (impaired lactation) mother. BP in male offspring was determined by tail cuff at 8, 12, and 20 wk of age, with glomerular number and volume (Cavalieri/Physical Dissector method) and renal angiotensin II type 1 receptor (AT(1)R) mRNA expression (real-time PCR) determined at 6 mo. Restricted-on-restricted male offspring developed hypertension (+16 mmHg) by 20 wk together with a nephron deficit (-26%) and glomerular hypertrophy (P < 0.05). In contrast, providing a normal lactational environment to restricted offspring improved postnatal growth and prevented the nephron deficit and hypertension. Reduced-on-restricted pups that were born of normal weight but with impaired growth during lactation subsequently grew faster, developed hypertension (+16 mmHg), had increased AT(1A)R and AT(1B)R mRNA expression (P < 0.05), but had no nephron deficit. Our study identifies the prenatal and postnatal nutritional environments in the programming of adult hypertension, associated with distinct renal changes. It is shown for the first time that a prenatally induced nephron deficit can be restored by correcting growth restriction during lactation.

                Author and article information

                S. Karger AG
                November 2008
                13 June 2008
                : 88
                : 4
                : 287-292
                aDepartment of Physiology, The University of Melbourne, Melbourne, Vic., bMothers and Babies Research Centre, University of Newcastle, Newcastle, N.S.W., cDepartment of Physiology, Monash University, Clayton, Vic., Australia
                139771 Neuroendocrinology 2008;88:287–292
                © 2008 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 1, References: 27, Pages: 6
                Neurotoxicity and Neuroprotection


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