Publications (10)38.16 Total impact
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Article: Vulnerability of the fetal primate brain to moderate reduction in maternal global nutrient availability.
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ABSTRACT: Moderate maternal nutrient restriction during pregnancy occurs in both developing and developed countries. In addition to poverty, maternal dieting, teenage pregnancy, and uterine vascular problems in older mothers are causes of decreased fetal nutrition. We evaluated the impact of global 30% maternal nutrient reduction (MNR) on early fetal baboon brain maturation. MNR induced major cerebral developmental disturbances without fetal growth restriction or marked maternal weight reduction. Mechanisms evaluated included neurotrophic factor suppression, cell proliferation and cell death imbalance, impaired glial maturation and neuronal process formation, down-regulation of gene ontological pathways and related gene products, and up-regulated transcription of cerebral catabolism. Contrary to the known benefits from this degree of dietary reduction on life span, MNR in pregnancy compromises structural fetal cerebral development, potentially having an impact on brain function throughout life.Proceedings of the National Academy of Sciences 02/2011; 108(7):3011-6. · 9.68 Impact Factor -
Article: Adverse effects of antenatal glucocorticoids on cerebral myelination in sheep.
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ABSTRACT: To determine in fetal sheep the effect of betamethasone on myelination in relation to stage of myelination, number of treatment courses, dose, and route of administration. Fetal expression of myelin basic protein (MBP), a marker of mature oligodendrocytes and myelin, was determined between 0.27 and 0.93 gestation. Short-term betamethasone effects were examined 24 hours after one maternal intramuscular treatment course (weight adjusted to equal the clinical dose of 2 x 8 mg betamethasone to a 70-kg woman) at 0.63, 0.75, and 0.87 gestation or after continuous 48-hour fetal intravenous infusion at 0.75 and 0.87 gestation. Lasting effects were examined 20 days after one and two treatment courses weight-adapted to the clinical dose of 2 x 8 mg or 2 x 12 mg betamethasone at 0.75 gestation. Myelin basic protein immunoreactivity was first detected in the internal capsule at 0.53 gestation, followed by the centrum semiovale, the superficial white matter, and corpus callosum at 0.63 gestation. Within 24 hours after treatment, betamethasone reduced the number of mature oligodendrocytes and MBP immunoreactivity. The effect decreased with gestational age. Maternal and fetal betamethasone administration had similar effects. Loss of MBP immunoreactivity was not reversed 20 days after two treatment courses, independent of dose. Betamethasone-induced delayed cerebral myelination is dependent on the stage of brain development in sheep. Betamethasone-related disturbances in myelination and any potential contribution to childhood behavior deficits need to be confirmed in clinical studies.Obstetrics and Gynecology 02/2009; 113(1):142-51. · 4.73 Impact Factor -
Article: Betamethasone-related acute alterations of microtubule-associated proteins in the fetal sheep brain are reversible and independent of age during the last one-third of gestation.
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ABSTRACT: The purpose of this study was to examine whether glucocorticoid effects on neuronal cytoskeleton, which we have shown previously at 0.87 gestation when the hypothalamo-pituitary-adrenal axis matures, are age-dependent and reversible. Fetal sheep received 3.3 microg kg(-1) h(-1) betamethasone (n = 10) or saline solution (n = 9) intravenously over 48 hours at 0.75 gestation (ie, before the hypothalamo-pituitary-adrenal axis matures and when betamethasone is administered clinically). Betamethasone diminished microtubule-associated protein (MAP) 1B and 2 immunoreactivity in the frontal neocortex and caudate putamen (P < .05) and MAP2 in the hippocampus (P < .05), which is similar to the effects that are seen at 0.87 gestation. In agreement, the number of glucocorticoid receptors did not differ at both ages. Loss of MAP1B and MAP2 immunoreactivity was not accompanied by neuronal death and was reversible within 24 hours. Alteration of neuronal cytoskeletal proteins caused by antenatal betamethasone exposure is transient and independent of age during late gestation.American journal of obstetrics and gynecology 07/2007; 196(6):553.e1-6. · 3.28 Impact Factor -
Article: Lack of effect of antenatal glucocorticoid therapy in the fetal baboon on cerebral cortical glucose transporter proteins.
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ABSTRACT: Maternal antenatal glucocorticoid therapy is used to accelerate lung maturation of immature babies at risk of preterm delivery. It acutely affects brain activity of the human fetus and reduces the immunoreactivity of neurocytoskeletal and synaptic proteins in the fetal baboon brain. These effects might be based on cerebral energy failure due to a decreased neuronal glucose uptake that has been shown in vitro. Glucose uptake into the brain is selectively facilitated by GLUT1 expressed in the blood-brain barrier and GLUT3 expressed in the neuronal membrane. Immunohistochemical distribution of GLUT1 and GLUT3 were examined in the frontal neocortex of the fetal baboon brain at 0.73 gestation (i.e. similar to 28 weeks of human gestation) after maternal betamethasone administration, mimicking the clinical dose regimen. Betamethasone did not alter GLUT1 and GLUT3 immunoreactivity. The results suggest that inhibition of glucose uptake is not the mechanism for the cerebral effects of antenatal glucocorticoids.Journal of Medical Primatology 03/2007; 36(1):17-20. · 1.30 Impact Factor -
Article: Glucose transporter proteins GLUT1 and GLUT3 like immunoreactivities in the fetal sheep brain are not reduced by maternal betamethasone treatment.
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ABSTRACT: Synthetic glucocorticoids administered to accelerate fetal lung maturation in threatened preterm delivery change electrocortical brain activity in the human and sheep fetus and alter structural neuronal proteins in fetal baboon and sheep. We hypothesized that these changes are due to a decreased amount of glucose transporter proteins (GLUT). Glucose uptake into cerebral neurons is selectively facilitated by glucose transporter protein GLUT1 in the blood brain barrier and GLUT3 in neuronal membranes. GLUT1 and GLUT3 immunoreactivity was examined in fetal sheep brain sections of the frontal neocortex, caudate putamen and hippocampus at 0.73 gestation after fetal exposure to betamethasone by direct fetal intravenous infusion or maternal intramuscular injections at the clinically relevant dosage. Betamethasone did not alter GLUT1 and GLUT3 immunoreactivity in any of the brain regions investigated, independently of the dose and route of administration. These data indicate that alteration of GLUT expression is unlikely to explain the cerebral functional effects of antenatal glucocorticoids.Neuroscience Letters 09/2006; 403(3):261-5. · 2.11 Impact Factor -
Article: Motor improvements after focal cortical ischemia in adult rats are mediated by compensatory mechanisms.
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ABSTRACT: Initial functional impairments after cerebral ischemia often improve considerably during the early period after the insult. Although pathological changes associated with post-lesion improvements have been widely investigated, it has not been resolved whether behavioral improvement represents true restoration of function (recovery) or development of new strategies (compensation). This study investigated whether early motor improvements after focal cerebral ischemia reflect recovery or compensation. Adult female Wistar rats were trained to retrieve food pellets in a skilled reaching task prior to receiving a unilateral cortical infarction induced by photothrombosis in forelimb motor cortex. Animals were continuously tested in the reaching task up to 3 weeks after lesion. The end point measures revealed that reaching success rates remained at pre-lesion levels, however, qualitative analysis of reaching movements indicated permanent changes in forelimb movement patterns. Similar observations were made in a skilled walking task and a test for forelimb asymmetry. These data indicate that lesion animals adopted alternative movement strategies in order to successfully perform the tasks. The changes in postoperative performance were compared to anatomical data in individual animals. The finding that reaching success was not related to lesion size supports the idea that the degree of adaptive behavior after cortical ischemia depends on plastic properties of the remaining intact tissue.Behavioural Brain Research 08/2005; 162(1):71-82. · 3.42 Impact Factor -
Article: Recovery of glucocorticoid-related loss of synaptic density in the fetal sheep brain at 0.75 of gestation
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ABSTRACT: Antenatal glucocorticoids routinely used to accelerate fetal lung maturation in human pregnancy at risk of preterm delivery decrease synaptic density and complex electrocortical activity in the fetal sheep brain at 0.87 gestation. We examined whether the effects of betamethasone on synaptic density depend on maturation of hypothalamo–pituitary–adrenal (HPA) axis and whether these effects are reversible. Betamethasone infusion to fetal sheep comparable to the dose used clinically (3.3 μg kg−1 h−1 over 48 h) at 0.75 gestation and, thus, before the prepartum increase of cortisol, reduced synaptophysin immunoreactivity (SY-IR) in the frontal neocortex, caudate putamen and hippocampus (P<0.05). Loss of SY-IR exceeded that shown previously at 0.87 gestation (P<0.05). It was not accompanied by neuronal damage and was reversible within 24 h. In conclusion, fetal betamethasone exposure induces a gestational age-dependent decrease of synaptic density that is transient and more severe in younger fetuses.Neuroscience Letters 07/2004; · 2.11 Impact Factor -
Article: Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain.
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ABSTRACT: Glucocorticoids have been used for 30 years to accelerate fetal lung maturation in human pregnancy at risk of preterm delivery. Exposure to inappropriate levels of steroid, however, leads to altered maturation of the cardiovascular, metabolic and central nervous systems. The effects of betamethasone on neuronal development and function were determined in the fetal baboon brain by examination of cytoskeletal microtubule associated proteins (MAPs) and the presynaptic marker protein synaptophysin. At 0.73 gestation, commencing 28 weeks of gestation, pregnant baboons received four doses of saline (n = 8) or 87.5 microg (kg body weight)(-1) betamethasone I.M. (n = 7) 12 h apart. This dose is equivalent to 12 mg betamethasone administered daily over two consecutive days to a 70 kg woman. Baboons underwent Caesarean section 12 h after the last injection. Paraffin sections of the fetal neocortex and the underlying white matter were labelled immunohistochemically against MAP1B, MAP2abc, MAP2ab and synaptophysin and stained histochemically with hematoxylin-eosin and silver. Tissue staining was quantified morphometrically. Betamethasone exposure resulted in decreased immunoreactivity (IR) of MAP1B by 34.3 % and MAP2abc by 34.1 % (P < 0.05). Loss of MAP2 IR was due to loss of IR of the juvenile isoform MAP2c (P < 0.05). MAP1B and MAP2c are involved in neuritogenesis and neuronal plasticity. Synaptophysin IR was reduced by 51.8 % (P < 0.01). These changes might reflect functional neuronal disturbances because they were not accompanied by an alteration of the density of neurofibrils or neuronal necrosis. These results are in agreement with earlier findings of alterations of cytoskeletal proteins and presynaptic terminals in the fetal sheep brain after betamethasone infusion directly to the fetus and support a common effect of inappropriate fetal exposure to glucocorticoids on neuronal cytoskeleton and synapses in mammalian species.The Journal of Physiology 02/2003; 547(Pt 1):117-23. · 4.72 Impact Factor -
Article: Developmental changes in cerebral autoregulatory capacity in the fetal sheep parietal cortex.
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ABSTRACT: We validated laser Doppler flowmetry (LDF) for long-term monitoring and detection of acute changes of local cerebral blood flow (lCBF) in chronically instrumented fetal sheep. Using LDF, we estimated developmental changes of cerebral autoregulation. Single fibre laser probes (0.4 mm in diameter) were implanted in and surface probes were placed on the parietal cerebral cortex at 105 +/- 2 (n = 7) and 120 +/- 2 days gestational age (dGA, n = 7). Basal lCBF was monitored over 5 days followed by a hypercapnic challenge (fetal arterial partial pressure of CO(2), P(a,CO2): 83 +/- 3 mmHg) during which lCBF changes obtained by LDF were compared to those obtained with coloured microspheres (CMSs). Mean arterial blood pressure (MABP) was increased and decreased using phenylephrine and sodium nitroprusside at 110 +/- 2 and 128 +/- 2 dGA. Intracortical and cortical surface laser probes gave stable measurements over 5 days. The lCBF increase during hypercapnia obtained by LDF correlated well with flows obtained using CMS (r = 0.89, P < 0.01). The signals of intracortical and surface laser probes also correlated well (r = 0.91, P < 0.01). Gliosis of 0.35 +/- 0.06 mm around the tip of intracortical probes did not affect the measurements. The range of MABP over which cerebral autoregulation was observed increased from 20-48 mmHg at 110 dGA to 35 to > 95 mmHg at 128 dGA (P < 0.05). Since MABP increased from 33 to 54 mmHg over this period (P < 0.01), the range between the lower limit of cerebral autoregulation and the MABP increased from 13 mmHg at 110 dGA to 19 mmHg at 128 dGA (P < 0.01). LDF is a reliable tool to assess dynamic changes in cerebral perfusion continuously in fetal sheep.The Journal of Physiology 04/2002; 539(Pt 3):957-67. · 4.72 Impact Factor -
Article: Antenatal betamethasone treatment reduces synaptophysin immunoreactivity in presynaptic terminals in the fetal sheep brain
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ABSTRACT: Knowledge of morphofunctional effects on the fetal brain induced by exogenous glucocorticoids is limited. Recently, we reported alterations of both the neuronal cytoskeleton and electrocortical function in the ovine fetal brain after antenatal betamethasone treatment in doses used in perinatal medicine. In the present study we examined whether these changes are accompanied by morphological alterations of synapses. Chronically instrumented fetal sheep at 0.87 of gestation were treated either with isotonic saline (n=7) or 10 μg/h betamethasone (n=7) over 48 h administered directly to the fetal jugular vein. Paraffin sections of the frontal neocortex, caudate putamen and hippocampus were stained with a monoclonal antibody against synaptophysin, a specific membrane protein of presynaptic vesicles and quantified morphometrically. Synaptophysin-like immunoreactivity (synaptophysin-LI) showed a widespread granular pattern in the neuropil. Betamethasone exposure reduced synaptophysin-LI in the frontal neocortex, caudate putamen and hippocampus by 46.9, 41.0 and 55.4%, respectively, (P<0.05) that was not accompanied by irreversible neuronal damage. These results suggest that clinical doses of betamethasone have acute effects on presynaptic terminals in the fetal sheep brain that could contribute to the altered complexity of electrocortical function that we have shown previously to occur following fetal exposure to betamethasone.Neuroscience Letters 01/2001; · 2.11 Impact Factor
Top co-authors
Top Journals
Institutions
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2002–2011
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Friedrich-Schiller-Universität Jena
- Klinik für Neurologie
Jena, Thuringia, Germany
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2001
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Cornell University
New York City, NY, USA
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