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 (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 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 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.

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 How long is sufficient for optimal neuroprotection with cerebral cooling after ischemia in fetal sheep?

2017 ◽  
Vol 38 (6) ◽  
pp. 1047-1059 ◽  
Author(s):  
Joanne O Davidson ◽  
Vittoria Draghi ◽  
Sean Whitham ◽  
Simerdeep K Dhillon ◽  
Guido Wassink ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Ischemia ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Close Association ◽  
Global Cerebral Ischemia ◽  
Fetal Sheep ◽  
Head Cooling ◽  
Improved Outcomes ◽  
Eeg Power

The optimal duration of mild “therapeutic” hypothermia for neonates with hypoxic-ischemic encephalopathy is surprisingly unclear. This study assessed the relative efficacy of cooling for 48 h versus 72 h. Fetal sheep (0.85 gestation) received sham ischemia (n = 9) or 30 min global cerebral ischemia followed by normothermia (n = 8) or delayed hypothermia from 3 h to 48 h (n = 8) or 72 h (n = 8). Ischemia was associated with profound loss of electroencephalogram (EEG) power, neurons in the cortex and hippocampus, and oligodendrocytes and myelin basic protein expression in the white matter, with increased Iba-1-positive microglia and proliferation. Hypothermia for 48 h was associated with improved outcomes compared to normothermia, but a progressive deterioration of EEG power after rewarming compared to 72 h of hypothermia, with impaired neuronal survival and myelin basic protein, and more microglia in the white matter and cortex. These findings show that head cooling for 48 h is partially neuroprotective, but is inferior to cooling for 72 h after cerebral ischemia in fetal sheep. The close association between rewarming at 48 h, subsequent deterioration in EEG power and increased cortical inflammation strongly suggests that deleterious inflammation can be reactivated by premature rewarming.

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