Biomedical subjects

P D Gluckman

Publications and source records attributed to P D Gluckman.

At least 19 recordsLinked to original sources

PubMed2007

HOXA1-stimulated oncogenicity is mediated by selective upregulation of components of the p44/42 MAP kinase pathway in human mammary carcinoma cells.

Expression of homeobox A1 (HOXA1) results in oncogenic transformation of immortalized human mammary epithelial cells with aggressive tumor formation in vivo. However, the mechanisms by which HOXA1 mediates oncogenic transformation is not well defined. To identify molecules that could potentially be involved in HOXA1-mediated oncogenic transformation, microarray analysis was utilized to characterize and compare the gene expression pattern in response to forced expression or depletion of HOXA1 in human mammary carcinoma cells. Gene expression profiling identified that genes involved in the p44/42 mitogen-activated protein (MAP) kinase activation pathway (GRB2, MAP kinase kinase (MEK1) and SDFR1) or p44/42 MAP kinase-regulated genes (IER3, EPAS1, PCNA and catalase) are downstream expression targets of HOXA1. Forced expression of HOXA1 increased GRB2 and MEK1 mRNA and protein expression and increased p44/42 MAP kinase phosphorylation, activity and Elk-1-mediated transcription. Use of a MEK1 inhibitor demonstrated that increased p44/42 MAP kinase activity is required for the HOXA1-mediated increase in cell proliferation, survival, oncogenicity and oncogenic transformation. Thus, modulation of the p44/42 MAP kinase pathway is one mechanism by which HOXA1 mediates oncogenic transformation of the human mammary epithelial cell.

Breast Neoplasms↗

PubMed2006

Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat.

Growth hormone (GH) therapy is often associated with adverse side effects, including impaired insulin sensitivity. GH treatment of children with idiopathic short stature does not lead to an optimized final adult height. It has been demonstrated that FFA reduction induced by pharmacological antilipolysis can stimulate GH secretion per se in both normal subjects and those with GH deficiency. However, to date, no investigation has been undertaken to establish efficacy of combination treatment with GH and FFA regulators on linear body growth. Using a model of maternal undernutrition in the rat to induce growth-restricted offspring, we investigated the hypothesis that combination treatment with GH and FFA regulators can enhance linear body growth above that of GH alone. At postnatal day 28, male offspring of normally nourished mothers (controls) and offspring born with low birth weight [small for gestational age (SGA)] were treated with saline, GH, or GH (5 mg.kg(-1).day(-1)) in combination with acipimox (GH + acipimox, 20 mg.kg(-1).day(-1)) or fenofibrate (GH + fenofibrate, 30 mg.kg(-1).day(-1)) for 40 days. GH plus acipimox treatment significantly enhanced linear body growth in the control and SGA animals above that of GH, as quantified by tibial and total body length. Treatment with GH significantly increased fasting plasma insulin, insulin-to-glucose ratio, and plasma volumes in control and SGA animals but was not significantly different between saline and GH-plus-acipimox-treated animals. GH-induced lipolysis was blocked by GH plus acipimox treatment in both control and SGA animals, concomitant with a significant reduction in fasting plasma FFA and insulin concentrations. This is the first study to show that GH plus acipimox combination therapy, via pharmacological blocking of lipolysis during GH exposure, can significantly enhance the efficacy of GH in linear growth promotion and ameliorate unwanted metabolic side effects.

Animals↗

PubMed2006

Changing times: the evolution of puberty.

An evolutionary and life history perspective is used to consider the evolution of puberty. The age of menarche would have evolved by the Neolithic to be matched to social maturity. It is suggested that in developed countries menarche is now returning to a similar age as in the Neolithic as infection and undernutrition, features of post-Neolithic society, have reduced impact. But recently the psychosocial expectations on adolescents in western societies have changed and social maturity now significantly follows menarche. The implications of the developing mismatch between the ages of biological puberty and social maturation are discussed. Evolutionary arguments are presented to explain the unique pubertal growth spurt of humans. Moreover, a life history perspective can reconcile the apparently conflicting observations that both poor fetal growth and better childhood nutrition are associated with earlier menarche.

Age Factors↗

PubMed2006

The consequences of being born small - an adaptive perspective.

Absolute definitions of fetal growth are being replaced by definitions that focus on an optimal life-course trajectory. The fetus makes responses to its environment that are determined by the maternal macro-environment, health and physiology. The processes of maternal constraint create significant variations within the normal range of maternal environments and function, and in the fetal environment, which are reflected in different patterns of growth. Deficient nutrient provision may induce immediate adaptation in the form of fetal growth impairment, but will also induce adaptive responses that have evolved for predictive advantage; that is, for a later phase of the life cycle. This latter class of response, probably mediated by epigenetic processes, explains many outcomes of a less-than-optimal pregnancy, including impaired growth, increased visceral obesity, impaired cognitive development, advanced maturation and a greater risk of metabolic and related disease in later life. While these adaptive processes evolved and were appropriate in the environments of prehistory, they are increasingly mismatched with modern environments. Such considerations suggest different approaches to intervention and prevention in population-specific contexts.

Adaptation, Physiological↗

PubMed2005

The insulin-like growth factor system and its pleiotropic functions in brain.

In recent years, much interest has been devoted to defining the role of the IGF system in the nervous system. The ubiquitous IGFs, their cell membrane receptors, and their carrier binding proteins, the IGFBPs, are expressed early in the development of the nervous system and are therefore considered to play a key role in these processes. In vitro studies have demonstrated that the IGF system promotes differentiation and proliferation and sustains survival, preventing apoptosis of neuronal and brain derived cells. Furthermore, studies of transgenic mice overexpressing components of the IGF system or mice with disruptions of the same genes have clearly shown that the IGF system plays a key role in vivo.

Animals↗

PubMed2005

Neonatal leptin treatment reverses developmental programming.

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this programming has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Reduced locomotor activity and hyperphagia contribute to the increased fat mass. Using this model of maternal undernutrition, we investigated the effects of neonatal leptin treatment on the metabolic phenotype of adult female offspring. Leptin treatment (rec-rat leptin, 2.5 microg/g.d, sc) from postnatal d 3-13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring, and normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in programmed offspring in adult life in contrast to saline-treated offspring of undernourished mothers who developed all these features on a high-fat diet. Neonatal leptin had no demonstrable effects on the adult offspring of normally fed mothers. This study suggests that developmental metabolic programming is potentially reversible by an intervention late in the phase of developmental plasticity. The complete normalization of the programmed phenotype by neonatal leptin treatment implies that leptin has effects that reverse the prenatal adaptations resulting from relative fetal undernutrition.

Absorptiometry, Photon↗

PubMed2005

Treatment in animal models.

It is now well established that neurons and other cell types may die many hours or even days after hypoxic-ischemic injury due to activation of programmed cell death (apoptotic) pathways. The potent anti-apoptotic factor IGF-1 and its binding proteins and receptors are intensely induced within damaged brain regions following brain injury suggesting a possible a role for IGF-1 in endogenous brain recovery. Exogenous administration of IGF-1 within a few hours after brain injury has now been shown to be protective in both grey and white matter, and leads to improved long-term neurological function. The limited window of opportunity for treatment with IGF-1 can be extended by spontaneous mild post-hypoxic hypothermia, probably due to delayed evolution of apoptotic processes. The efficacy of IGF-1 is specific to particular cellular phenotypes and brain regions, and its neuroprotective effects are mediated by IGF-1 receptors and binding proteins. Intriguingly its naturally cleaved N-terminal tripeptide (glycine-proline-glutamate, GPE) has been demonstrated to be neuroprotective after both central and peripheral administration. Peripheral administration of GPE also prevents the loss of dopamine neurons and improves long-term functional recovery following 6-OHDA lesion. However, GPE is unlikely to contribute significantly to the direct effects of IGF-1.

Animals↗

PubMed2004

Neuroprotective effects of the N-terminal tripeptide of insulin-like growth factor-1, glycine-proline-glutamate (GPE) following intravenous infusion in hypoxic-ischemic adult rats.

The N-terminal tripeptide of insulin-like growth factor-1, GPE is neuroprotective when given intracerebroventricularly 2 h after hypoxic-ischemic (HI) brain injury in rats. We have now examined whether GPE can cross the blood-brain barrier and exert neuroprotective actions following intravenous administration. Following a single bolus intravenous injection, GPE was rapidly metabolized and cleared from the circulation. The short half-life (<2 min) in blood was subsequently associated with modest and inconsistent neuroprotection. In contrast, potent neuroprotection of GPE was consistently observed in all brain regions examined following 4 h intravenous infusion (12 mg/kg). The neuroprotective effects of GPE after infusion showed a broad effective dose range (1.2-120 mg/kg) and an extended window of treatment to 7-11 h after injury. The central penetration of GPE after intravenous infusion was injury-dependent. GPE also improved long-term somatofunction with a comparable neuronal outcome. GPE reduced both caspase-3-dependent and -independent apoptosis in the hippocampus. Treatment with GPE also inhibited microglial proliferation and prevented the injury-induced loss of astrocytes. In conclusion, the neuroprotective actions of GPE infusion were global, robust and displayed a broad effective dose range and treatment window. GPE's activity included the prevention of neuronal apoptosis, promotion of astrocyte survival and inhibition of microglial proliferation. With injury specific central penetration, GPE has considerable promise as a systemic neuroprotective treatment after acute encephalopathies.

Animals↗

PubMed2004

Serum insulin-like growth factor-I concentrations in late middle age: no association with birthweight in three UK cohorts.

BACKGROUND: Small body size at birth and during infancy is associated with an increased risk of adult osteoporosis and cardiovascular disease. Fetal programming of the growth hormone-insulin-like growth factor (GH-IGF) axis may provide a mechanism for these epidemiological findings. AIMS: To determine whether measurements of GH and IGF-I in late middle age were related to size at birth and in infancy. METHODS: Overnight urinary GH excretion and fasting serum IGF-I were measured in 309 men and 193 women from Hertfordshire (born 1920-1930) for whom birthweight and weight at 1 year were recorded. Serum IGF-I was measured in men and women from Preston (n=254, born 1935-1943) and Sheffield (n=215, born 1939-1940) whose birthweight and other birth measurements were recorded. RESULTS: Urinary GH and serum IGF-I were not related to birthweight, other measurements at birth, or weight at 1 year. CONCLUSION: In contrast to previous studies in children or young adults, these data do not support the hypothesis that IGF-I concentrations are programmed by intra-uterine events, as assessed by birthweight, in late middle age.

Aged↗

PubMed2003

Pharmacokinetics of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor-1, in rats.

Glycine-proline-glutamate (GPE) is the N-terminal tripeptide of insulin-like growth factor-1 and has been shown to be neuroprotective following ischemia-induced brain injury. The pharmacokinetics of GPE were studied in adult rats since GPE is a candidate for use in neuroprotection therapies. To measure plasma concentrations of GPE a novel radioimmunoassay was developed whereby GPE was initially derivatized with Bolton and Hunter reagent before use in a standard homologous assay against the Bolton and Hunter iodinated form. The derivatized GPE radioimmunoassay showed a 83% recovery of unlabeled GPE and complete parallel displacement with rat plasma. The simplicity and speed of the assay described here indicate an exciting new use for a previously described technology. The pharmacokinetic studies were conducted in adult rats using a single bolus intravenous injection of GPE at 30 or 100 mg/kg and showed that GPE was rapidly cleared from the circulation. In addition, evidence of the route of the metabolic degradation of GPE is presented. The findings presented here are the first description of the pharmacokinetics of GPE and suggest that, because of its very short half-life in plasma, continuous intravenous infusion of GPE may be the preferred route of administration for use in future neuroprotection therapies.

Animals↗

PubMed2003

Insulin-like growth factor-1 and post-ischemic brain injury.

Insulin-like growth factor-1 (IGF-1) is a naturally occurring neurotrophic factor that plays an important role in promoting cell proliferation and differentiation during normal brain development and maturation. The present review examines recent evidence that endogenous IGF-1 also plays a significant role in recovery from insults such as hypoxia-ischemia and that giving additional exogenous IGF-1 can actively ameliorate damage. It is now well established that neurons and other cell types die many hours or even days after initial injury due to activation of programmed cell death pathways. IGF-1 and its binding proteins and receptors are intensely induced within damaged brain regions following brain injury, suggesting a possible a role for IGF-1 in brain recovery. Exogenous administration of IGF-1 within a few hours after brain injury is now known to be protective in both gray and white matter and leads to improved somatic function. In contrast, pre-treatment is ineffective, likely reflecting limited intracerebral penetration of IGF-1 into the uninjured brain. The neuroprotective effects of IGF-1 are mediated by IGF-1 receptors and its binding proteins and are specific to particular cellular phenotypes and brain regions. The window of opportunity for treatment with IGF-1 is limited to a few hours after normothermic brain injury, reflecting its specific actions on early, intracellular events in the apoptotic cascade. However, injury-associated mild post-hypoxic hypothermia, which delays the development of cell death, can shift and dramatically extend the window of opportunity for delayed treatment with IGF-1. Such a combined approach is likely to be essential for any clinical treatment.

Animals↗

PubMed2003

Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition.

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is now increasing evidence that alterations in the fetal environment have long-term consequences on metabolic and endocrine pathophysiology in adult life. This process has been termed "fetal programming," and we have shown that undernutrition of the mother during gestation leads to obesity, hypertension, hyperphagia, hyperinsulinemia, and hyperleptinemia in offspring. Using this model of maternal undernutrition throughout pregnancy, we investigated whether prenatal influences may lead to alterations in postnatal locomotor behavior, independent of postnatal nutrition. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (ad libitum group) or at 30% of ad libitum intake (undernourished group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [control or hypercaloric (30% fat)]. At ages of 35 days, 145 days, and 420 days, voluntary locomotor activity was assessed. At all ages studied, offspring from undernourished mothers were significantly less active than offspring born of normal birth weight for all parameters measured, independent of postnatal nutrition. Sedentary behavior in programmed offspring was exacerbated by postnatal hypercaloric nutrition. This work is the first to clearly separate prenatal from postnatal effects and shows that lifestyle choices themselves may have a prenatal origin. We have shown that predispositions to obesity, altered eating behavior, and sedentary activity are linked and occur independently of postnatal hypercaloric nutrition. Moreover, the prenatal influence may be permanent as offspring of undernourished mothers were still significantly less active compared with normal offspring at an advanced adult age, even in the presence of a healthy diet throughout postnatal life.

Animal Feed↗

PubMed2003

Chronic pulsatile infusion of growth hormone to growth-restricted fetal sheep increases circulating fetal insulin-like growth factor-I levels but not fetal growth.

Intra-uterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity. Postnatally, growth hormone (GH) increases growth, increases circulating insulin-like growth factor (IGF)-I levels, and alters metabolism. Our aim was to determine if GH infusion to IUGR fetal sheep would alter fetal growth and metabolism, and thus provide a potential intra-uterine treatment for the IUGR fetus. We studied three groups of fetuses: control, IUGR+ vehicle and IUGR+GH (n=5 all groups). IUGR was induced by repeated embolisation of the placental vascular bed between 110 and 116 days of gestation (term=145 days). GH (3.5 mg/kg/day) or vehicle was infused in a pulsatile manner from 117 to 127 days of gestation. Embolisation reduced fetal growth rate by 25% (P<0.01) and reduced the weight of the fetal liver (20%), kidney (23%) and thymus (31%; all P<0.05). GH treatment further reduced the weight of the fetal kidneys (32%) and small intestine (35%; both P<0.04), but restored the relative weight of the fetal thymus and liver (P<0.05). Embolisation decreased fetal plasma IGF-I concentrations (48%, P<0.001) and increased IGF binding protein 1 (IGFBP-1) concentrations (737%, P<0.002). GH treatment restored fetal plasma IGF-I concentrations to control levels, while levels in IUGR+vehicle fetuses stayed low (P<0.05 vs control). IGFBP-1 and IGFBP-2 concentrations were about sevenfold lower in amniotic fluid than in fetal plasma, but amniotic and plasma concentrations were closely correlated (r=0.75, P<0.0001 and r=0.55 P<0.0001 respectively). Embolisation transiently decreased fetal blood oxygen content (40%, P<0.002), and increased blood lactate concentrations (213%, P<0.04). Both returned to pre-embolisation levels after embolisation stopped, but blood glucose concentrations declined steadily in IUGR+vehicle fetuses. GH treatment maintained fetal blood glucose concentrations at control levels. Our study shows that GH infusion to the IUGR fetal sheep restores fetal IGF-I levels but does not improve fetal growth, and further reduces the fetal kidney and intestine weights. Thus, fetal GH therapy does not seem a promising treatment stratagem for the IUGR fetus.

Animals↗

PubMed2001

Neuroprotective effects of the N-terminal tripeptide of IGF-1, glycine-proline-glutamate, in the immature rat brain after hypoxic-ischemic injury.

Insulin growth factor 1 (IGF-1) has an important role in brain development and is strongly expressed during recovery after a hypoxic-ischemic injury. Some of its central actions could be mediated through the N-terminal tripeptide fragment of IGF-1: Gly-Pro-Glu (GPE). The neuroprotective properties of GPE given after a moderate injury in the developing rat brain were evaluated and the binding sites of [(3)H]GPE characterised by autoradiography. After right unilateral injury, GPE or vehicle (V) was injected in the right lateral ventricle (i.c.v.) or in the peritoneal cavity (i.p.) of 21-day-old rats. The percentage of surviving neurons in CA1-2 of the hippocampus was higher in the animals treated with 30 microg of GPE i.c.v. (V: 7.7+/-4.9%, GPE: 26.4+/-7.5%, P=0.02) and 300 microg i.p. (V: 30.2+/-9.1%, GPE: 68.8+/-10.6%, P=0.02) than in animals receiving vehicle. I.p. injection of 300 microg of GPE (V: 78.4+/-7.5%, GPE: 88.4+/-3.2%, P=0.04) was also neuroprotective in the lateral cortex. I.c.v. injection of [(3)H]GPE suggested binding to glial cells in the white matter tracts, the cortex and striatum as opposed to neurons. Although the precise mode of action of GPE is unknown, this study suggests that local administration of GPE is neuroprotective after brain HI injury via glial cells. In addition, systemic administration of GPE showed a more widespread neuroprotective effect. GPE may represent a complementary pathway for central and systemic IGF-1's antiapoptotic effects.

Animals↗

PubMed2001

Growth hormone as a neuronal rescue factor during recovery from CNS injury.

There is growing evidence to suggest that growth hormone plays a role in the growth and development of the CNS. Specifically, growth hormone has been implicated in promoting brain growth, myelination, neuronal arborisation, glial differentiation and cognitive function. Here we investigate if growth hormone has a role in the recovery from an unilateral hypoxic-ischaemic brain injury. Using moderate (15 min hypoxia) and severe (60 min hypoxia) models of hypoxic-ischaemia in juvenile rats and standard immunohistochemical techniques, we found intense growth hormone-like immunoreactivity present within regions of cell loss by 3 days (P<0.05). Growth hormone-like immunoreactivity was observed on injured neurones, myelinated axons, glial cells within and surrounding infarcted tissue and on the choroid plexus plus ependymal cells within the injured hemisphere. The pattern of immunoreactivity suggests that (a) growth hormone (or a growth hormone-like substance) is transported via the cerebrospinal fluid and (b) that growth hormone (or a growth hormone-like substance) is acting in a neurotrophic manner specifically targeted to injured neurones and glia. To test this hypothesis we treated a moderate hypoxic-ischaemic brain injury with 20 microg of rat growth hormone by intracerebroventricular infusion starting 2 h after injury (n=12/group). After 3 days the animals were killed and the extent of neuronal loss quantified. Growth hormone treatment reduced neuronal loss in the frontoparietal cortex (P<0.001), hippocampus (P<0.01) and dorsolateral thalamus (P<0.01) but not in the striatum. This spatial distribution of the neuroprotection conveyed by growth hormone correlates with the spatial distribution of the constitutive neural growth hormone receptor, but not with the neuroprotection offered by insulin-like growth factor-I treatment in this model. These results suggest that some of the neuroprotective effects of growth hormone are mediated directly through the growth hormone receptor and do not involve insulin-like growth factor-I induction.In summary, we have found that a growth hormone-like factor increased in the brain in the days after injury. In addition, treatment with growth hormone soon after an hypoxic-ischaemic injury reduced the extent of neuronal loss. These results further suggest that a neural growth hormone axis is activated during recovery from injury and that this may act to restrict the extent of neuronal death.

Animals↗

PubMed2001

Insulin-like growth factor-1 improves somatosensory function and reduces the extent of cortical infarction and ongoing neuronal loss after hypoxia-ischemia in rats.

Treatment with insulin-like growth factor-1 has been demonstrated to reduce the extent of cortical infarction 5 days after hypoxic-ischemic brain injury. As neuronal death can be progressive and long lasting after initial injury, the present study examined the long-term effects of insulin-like growth factor-1 on late neuronal loss 20 days after hypoxic-ischemic injury, together with evaluating neurobehavioral outcome as assumed by somatosensory function. Unilateral brain injury was induced in adult rats by carotid artery ligation followed by 10 min of hypoxia (6% O2). A single dose of insulin-like growth factor-1 (50 microg) was administered intracerebroventricularly via a stereotaxically pre-fixed cannula 2 h after injury. A bilateral tactile stimulation test was used to examine the degree of somatosensory function at 3, 5, 10 and 20 days after the hypoxia in both insulin-like growth factor-1- (n=12) and its vehicle- (n=12) treated rats, along with sham-operated rats (n=9). Cortical infarction and percentage of selective neuronal loss in the cerebral cortex were examined 20 days after the hypoxic-ischemic injury in both treatment groups. Hypoxic-ischemic injury resulted in a significant delay in the time taken to contact the patch over the period examined (left/right ratio 5.1+/-0.79), particularly at 3 days (7.0+/-2.8) after the hypoxia, compared to sham-operated rats (1.1+/-0.9, P<0.05). The overall effect of insulin-like growth factor-1 in reducing the time taken to contact the patch was significant (P=0.03, 2.6+/-0.79) compared to the vehicle group. There was a trend towards a reduction of cortical infarction after insulin-like growth factor-1 treatment (P=0.058), however insulin-like growth factor-1 significantly reduced the percentage of selective neuronal loss (P=0.027) 20 days following the hypoxia. From these data we suggest that insulin-like growth factor-1 improves somatosensory function by reducing both the extent of cortical infarction and ongoing progressive neuronal death during brain recovery from hypoxic-ischemic injury.

Animals↗

PubMed2001

Hypoxic-ischemic brain injury in the newborn: pathophysiology and potential strategies for intervention.

There is increasing clinical and experimental data describing the evolution of hypoxic-ischemic encephalopathy in the perinatal period. Outcome to the fetus is determined not only by the impact of gross asphyxial insult, but also external factors that sensitize the brain to injury. Delayed neuronal and glial death occurring in the hours and days after the insult by apoptotic and related processes are observed following severe injury, and offer the most promise for pharmacological intervention. Furthermore, new technologies allow the identification of subtle insults with evolving encephalopathies that have implications for long-term neurological outcome. Application of this knowledge will allow us to identify strategies for early intervention and prevent the course of damage caused by hypoxic-ischemic injury.

Female↗

PubMed2001

Insulin-like growth factor-1 reduces postischemic white matter injury in fetal sheep.

Insulin-like growth factor-1 (IGF-1) is known to be important for oligodendrocyte survival and myelination. In the current study, the authors examined the hypothesis that exogenous IGF-1 could reduce postischemic white matter injury. Bilateral brain injury was induced in near-term fetal sheep by 30 minutes of reversible carotid artery occlusion. Ninety minutes after ischemia, either vehicle (n = 8) or a single dose of 3 microg IGF-1 (n = 9) was infused intracerebroventricularly over 1 hour. White matter changes were assessed after 4 days recovery in the parasagittal intragyral white matter and underlying corona radiata. Proteolipid protein (PLP) mRNA staining was used to identify bioactive oligodendrocytes. Glial fibrillary acidic protein (GFAP) and isolectin B-4 immunoreactivity were used to label astrocytes and microglia, respectively. Myelin basic protein (MBP) density and the area of the intragyral white matter tracts were determined by image analysis. Insulin-like growth factor-1 treatment was associated with significantly reduced loss of oligodendrocytes in the intragyral white matter (P < 0.05), with improved MBP density (P < 0.05), reduced tissue swelling, and increased numbers of GFAP and isolectin B-4 positive cells compared with vehicle treatment. After ischemia there was a close association of PLP mRNA labeled cells with reactive astrocytes and macrophages/microglia. In conclusion, IGF-1 can prevent delayed, postischemic oligodendrocyte cell loss and associated demyelination.

Animals↗