scholarly journals Insulin-Like Growth Factor (IGF)-1 Suppresses Oligodendrocyte Caspase-3 Activation and Increases Glial Proliferation after Ischemia in Near-Term Fetal Sheep

2003 ◽  
Vol 23 (6) ◽  
pp. 739-747 ◽  
Author(s):  
Yun Cao ◽  
Alistair Jan Gunn ◽  
Laura Bennet ◽  
David Wu ◽  
Sherly George ◽  
...  
Keyword(s):  
White Matter ◽  
Growth Factor ◽  
Caspase 3 ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep ◽  
Reactive Glia ◽  
Glial Proliferation ◽  
Bilateral Carotid ◽  
Near Term

Insulin-like growth factor (IGF-1) markedly increases myelination and glial numbers in white matter after ischemia in near-term fetal sheep; however, it is unclear whether this is due to reduced cell loss or increased secondary proliferation. Brain injury was induced in near-term fetal sheep by 30 minutes of bilateral carotid artery occlusion. Ninety minutes after the occlusion, fetuses were given, intracerebroventricularly, either a single dose of IGF-1 (either 3 or 30 μg), or 3 μg followed by 3 μg over 24 hours (3 + 3 μg). White matter was assessed 4 days after reperfusion. Three micrograms, but not 30 μg of IGF-1 prevented loss of oligodendrocytes and myelin basic protein density ( P < 0.001) compared to the vehicle-treated ischemia controls. No additional effect was observed in the 3 + 3 μg group. IGF-1 treatment was associated with reduced caspase-3 activation and increased glial proliferation in a similar dose-dependent manner. Caspase-3 was only expressed in oligodendrocytes that showed apoptotic morphology. Proliferating cell nuclear antigen co-localized with both oligodendrocytes and astrocytes and microglia. Thus, increased oligodendrocyte numbers after IGF-1 treatment is partly due to suppression of apoptosis, and partly to increased proliferation. In contrast, the increase in reactive glia was related only to proliferation. Speculatively, reactive glia may partly mediate IGF-1 white matter protection.

scholarly journals Window of Opportunity of Cerebral Hypothermia for Postischemic White Matter Injury in the Near-Term Fetal Sheep

2004 ◽  
Vol 24 (8) ◽  
pp. 877-886 ◽  
Author(s):  
Vincent Roelfsema ◽  
Laura Bennet ◽  
Sherly George ◽  
David Wu ◽  
Jian Guan ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Ischemia ◽  
Caspase 3 ◽  
Basic Protein ◽  
White Matter Injury ◽  
Window Of Opportunity ◽  
Reactive Microglia ◽  
Fetal Sheep ◽  
Near Term ◽  
Protein Density

Postresuscitation cerebral hypothermia is consistently neuroprotective in experimental preparations; however, its effects on white matter injury are poorly understood. Using a model of reversible cerebral ischemia in unanesthetized near-term fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.4±0.1°C to between 30 and 33°C), induced at different times after reperfusion and continued for 72 hours after ischemia, on injury in the parasagittal white matter 5 days after ischemia. Cooling started within 90 minutes of reperfusion was associated with a significant increase in bioactive oligodendrocytes in the intragyral white matter compared with sham cooling (41±20 vs 18±11 per field, P < 0.05), increased myelin basic protein density and reduced expression of activated caspase-3 (14±12 vs 91±51, P < 0.05). Reactive microglia were profoundly suppressed compared with sham cooling (4±6 vs 38±18 per field, P < 0.05) with no effect on numbers of astrocytes. When cooling was delayed until 5.5 hours after reperfusion there was no significant effect on loss of oligodendrocytes (24±12 per field). In conclusion, hypothermia can effectively protect white matter after ischemia, but only if initiated early after the insult. Protection was closely associated with reduced expression of both activated caspase-3 and of reactive microglia.

scholarly journals Interleukin-1 blockade attenuates white matter inflammation and oligodendrocyte loss after progressive systemic lipopolysaccharide exposure in near-term fetal sheep

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Sharmony B. Kelly ◽  
Vanesa Stojanovska ◽  
Valerie A. Zahra ◽  
Alison Moxham ◽  
Suzanne L. Miller ◽  
...  
Keyword(s):  
White Matter ◽  
Carotid Artery ◽  
Caspase 3 ◽  
Brain Inflammation ◽  
Brain Maturation ◽  
Fetal Sheep ◽  
Eeg Activity ◽  
Near Term ◽  
Artery Perfusion ◽  
Circulating Cytokines

Abstract Background Increased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). Methods Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n = 9). Sheep were euthanized 4 days after starting infusions for histology. Results LPS infusions increased circulating cytokines and were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P < 0.05 vs. control for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and caspase-3+ cells, and improved olig-2+ oligodendrocyte survival. Conclusion IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.

White Matter Protection with Insulin-Like Growth Factor 1 and Hypothermia Is Not Additive after Severe Reversible Cerebral Ischemia in Term Fetal Sheep

2011 ◽  
Vol 33 (3-4) ◽  
pp. 280-287 ◽  
Author(s):  
S. George ◽  
L. Bennet ◽  
L. Weaver-Mikaere ◽  
M. Fraser ◽  
J. Bouwmans ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Ischemia ◽  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep

scholarly journals Insulin-Like Growth Factor-1 Reduces Postischemic White Matter Injury in Fetal Sheep

2001 ◽  
Vol 21 (5) ◽  
pp. 493-502 ◽  
Author(s):  
Jian Guan ◽  
Laura Bennet ◽  
Shirley George ◽  
David Wu ◽  
Harry J. Waldvogel ◽  
...  
Keyword(s):  
White Matter ◽  
Growth Factor ◽  
Close Association ◽  
Proteolipid Protein ◽  
Cell Loss ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
White Matter Injury ◽  
Insulin Like Growth Factor ◽  
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 μg 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.

scholarly journals Rapid Alterations in Cerebral White Matter Lipid Profiles After Ischemic-Reperfusion Brain Injury in Fetal Sheep as Demonstrated by MALDI-Mass Spectrometry

2019 ◽  
Vol 22 (4) ◽  
pp. 344-355 ◽  
Author(s):  
Gina M Gallucci ◽  
Ming Tong ◽  
Xiaodi Chen ◽  
Barbara S Stonestreet ◽  
Amy Lin ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
White Matter ◽  
Lipid Composition ◽  
Lipid Profiles ◽  
Maldi Ms ◽  
Cerebral White Matter ◽  
Ionization Mass ◽  
Myelin Lipid ◽  
Fetal Sheep ◽  
Bilateral Carotid

Background Perinatal ischemia-reperfusion (I/R) injury of cerebral white matter causes long-term cognitive and motor disabilities in children. I/R damages or kills highly metabolic immature oligodendroglia via oxidative stress, excitotoxicity, inflammation, and mitochondrial dysfunction, impairing their capacity to generate and maintain mature myelin. However, the consequences of I/R on myelin lipid composition have not been characterized. Objective This study utilized matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to assess alterations in cerebral supraventricular white matter myelin lipid profiles in a fetal sheep model of perinatal I/R. Methods Fetal sheep (127 days gestation) were studied after 30 minutes of bilateral carotid artery occlusion followed by 4 (n = 5), 24 (n = 7), 48 (n = 3), or 72 (n = 5) hours of reperfusion, or sham treatment (n = 5). White matter lipids were analyzed by negative ion mode MALDI-MS. Results Striking I/R-associated shifts in phospholipid and sphingolipid expression occurred over the 72-hour time course with most responses detected within 4 hours of reperfusion and progressing at the 48- and 72-hour points. I/R decreased expression of phosphatidic acid and phosphatidylethanol amine and increased phosphatidylinositol, sulfatide, and lactosylceramide. Conclusions Cerebral I/R in mid-gestation fetal sheep causes rapid shifts in white matter myelin lipid composition that may reflect injury, proliferation, or recovery of immature oligodendroglia.

Intravenous infusion of insulin-like growth factor I in fetal sheep reduces hepatic IGF-I and IGF-II mRNAs

1996 ◽  
Vol 271 (6) ◽  
pp. R1632-R1637 ◽  
Author(s):  
K. L. Kind ◽  
J. A. Owens ◽  
F. Lok ◽  
J. S. Robinson ◽  
K. J. Quinn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Intravenous Infusion ◽  
Feedback Inhibition ◽  
Fetal Liver ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep ◽  
Igf I

Liver contains the highest concentrations of insulin-like growth factor (IGF) I mRNA in adult rats and sheep and is a major source of circulating IGF-I. In rats, inhibition of hepatic IGF-I production by exogenous IGF-I has been reported. In fetal sheep, skeletal muscle and liver are major sites of IGF-I synthesis and potential sources of circulating IGF-I. To determine whether feedback inhibition of IGF gene expression in fetal liver or muscle by IGF-I occurs, IGF-I and IGF-II mRNAs were measured in these tissues after intravenous infusion of recombinant human IGF-I into fetal sheep. Infusion of IGF-I (26 +/- 4 micrograms.h-1.kg-1; n = 6) or saline (n = 6) commenced on day 120 of pregnancy (term = 150 days) and continued for 10 days. Plasma concentrations of IGF-I were threefold higher in infused fetuses at 130 days of gestation (P < 0.0003), whereas those of IGF-II were unchanged. IGF-I infusion reduced the relative abundance of IGF-I mRNA (P < 0.0002) and IGF-II mRNA (P < 0.01) in fetal liver by approximately 50% but did not alter IGF-I or IGF-II mRNA in skeletal muscle. These results indicate that IGF-I inhibits the expression of both IGF-I and IGF-II genes in fetal liver and that IGF gene expression in fetal liver and muscle is differentially regulated by IGF-I.

scholarly journals The roles of glucagon-like peptide-2 and the intestinal epithelial insulin-like growth factor-1 receptor in regulating microvillus length

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Melanie A. Markovic ◽  
Patricia L. Brubaker
Keyword(s):  
Growth Factor ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Jejunal Mucosa ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Intestinal Epithelial ◽  
Glucagon Like Peptide ◽  
Long Acting ◽  
Downstream Mediator

Abstract Microvilli are tiny projections on the apical end of enterocytes, aiding in the digestion and absorption of nutrients. One of their key features is uniform length, but how this is regulated is poorly understood. Glucagon-like peptide-2 (GLP-2) has been shown to increase microvillus length but, the requirement of its downstream mediator, the intestinal epithelial insulin-like growth factor-1 receptor (IE-IGF-1R), and the microvillus proteins acted upon by GLP-2, remain unknown. Using IE-IGF-1R knockout (KO) mice, treated with either long-acting human (h) (GLY2)GLP-2 or vehicle for 11d, it was found that the h(GLY2)GLP-2-induced increase in microvillus length required the IE-IGF-1R. Furthermore, IE-IGF-1R KO alone resulted in a significant decrease in microvillus length. Examination of the brush border membrane proteome as well as of whole jejunal mucosa demonstrated that villin was increased with h(GLY2)GLP-2 treatment in an IE-IGF-1R-dependent manner. Under both basal conditions and with h(GLY2)GLP-2 treatment of the IE-IGF-1R KO mice, changes in villin, IRTKS-1, harmonin, β-actin, and myosin-1a did not explain the decrease in microvillus length, in either the brush border or jejunal mucosa of KO animals. Collectively, these studies define a new role for the IE-IGF-1R within the microvillus, in both the signaling cascade induced by GLP-2, as well as endogenously.

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