Animal Models of Perinatal Hypoxic-Ischemic Brain Damage

Yager, Jerome Y.; Ashwal, Stephen

doi:10.1016/j.pediatrneurol.2008.10.025

Cited by 118 publications

(86 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, this experimental weakness strengthens the translational value of the model, because it reproduces variability observed in human neonatal HI. 32 Because the brains in different species are very different in neuronal maturation, neuronal growth spurt, and vulnerability to HI, 33 it is important to compare findings between species. We aimed to define the window for HT neuroprotection in neonatal rats.…”

Section: Discussionmentioning

confidence: 99%

Immediate Hypothermia Is Not Neuroprotective After Severe Hypoxia-Ischemia and Is Deleterious When Delayed by 12 Hours in Neonatal Rats

Sabir

Scull-Brown²,

Liu³

et al. 2012

Stroke

132

152

View full text Add to dashboard Cite

T herapeutic hypothermia (HT) has become standard treatment for term newborns experiencing perinatal asphyxia.1 Randomized controlled trials have shown that HT significantly improves outcome after hypoxia-ischemia (HI). [2][3][4][5][6] Meta-analysis of these suggests that HT improves outcome more in the group with moderate rather than severe HI encephalopathy.7 HI encephalopathy develops during different phases. 8 Initial reperfusion restores cellular energy metabolism in ≈30 to 60 minutes. A latent phase of 6 to 12 hours follows, in which cellular energy metabolism is fully or partially restored 9 before a secondary decline in energy failure may occur. This secondary phase is characterized by excessive entry of Ca 2+ into cells, free radical production, excitotoxic amino acid release, inflammation, and activation of apoptotic pathways, [10][11][12] commencing within 24 hours and lasting days or weeks. These phases of injury and recovery are not strictly sequential, might overlap, and are likely to be changed by severity of injury or other conditions. 13 As previously shown in different animal models, HT during reperfusion and the latent phase is neuroprotective. [14][15][16] Clinical guidelines recommend that HT should be started within the first 6 hours after birth based on findings in a term-equivalent fetal sheep HI model 16,17 showing significant neuroprotection when HT was initiated before 5.5 hours after cerebral injury.8 There are few studies published about the effect of HT initiated late after HI of different severity, 8,18,19 and no study asks whether HT might increase injury if started very late. There might be species, age, and injury differences. In newborn pigs, delaying HT by 3 hours was ineffective. 20 In adult rat stroke models, delayed treatment up to 3 hours is neuroprotective. [21][22][23] Our aim was to investigate in moderate and severe unilateral brain injury in neonatal rats the effect of HT, the optimal duration of HT, and the effective time window of HT.Background and Purpose-Hypothermia (HT) for neonatal hypoxic-ischemic encephalopathy is advised to start within the first 6 hours after birth. There is some clinical evidence that HT is more effective against moderate than against severe hypoxic-ischemic encephalopathy, but it is unknown whether delayed HT beyond 6 hours is effective or even injurious. Methods-One-hundred seven 7-day-old rat pups underwent unilateral hypoxia-ischemia of moderate severity. Pups were randomized to receive 5 hours of normothermia (NT) or HT starting immediately, 3 hours, 6 hours, or 12 hours after the 90-minute hypoxic period. One-hundred five 7-day-old rat pups underwent severe hypoxia-ischemia lasting 150 minutes, followed by the same group design as mentioned. Relative area loss of the left/right hemisphere was measured after 1 week of survival. Results-In the moderate NT group, the mean area loss of the left hemisphere was 40.5%. Materials and Methods ProceduresAll procedures were performed under Home Office license in accordance with United Kingdom r...

show abstract

Section: Discussionmentioning

confidence: 99%

Immediate Hypothermia Is Not Neuroprotective After Severe Hypoxia-Ischemia and Is Deleterious When Delayed by 12 Hours in Neonatal Rats

Sabir

Scull-Brown²,

Liu³

et al. 2012

Stroke

132

152

View full text Add to dashboard Cite

show abstract

“…We used the Rice-Vannucci model (RVM), the most commonly used model to study HI brain injury in the developing brain (17). Rats (Wistar) aged 7-10 postnatal days correspond to term human newborn (14).…”

Section: Methodsmentioning

confidence: 99%

Lipopolysaccharide-Induced Preconditioning Against Ischemic Injury Is Associated With Changes in Toll-Like Receptor 4 Expression in the Rat Developing Brain

et al. 2011

View full text Add to dashboard Cite

Lipopolysaccharide (LPS) preconditioning reduces ischemic injury in adult brain by activating Toll-like receptor 4 (TLR-4). We sought to investigate the effect of brain maturity on the efficacy of LPS preconditioning against hypoxic-ischemic (HI) injury in the developing rat brain. Rat pups at the specified age were randomly assigned to LPS-treated (0.1 mg/kg) or saline-treated groups. HI injury was induced 48 h later by occluding the right common carotid artery followed by transient hypoxia. Brains were removed 1 wk after HI injury, and infarct volumes were compared between the two groups. TLR-4 expression was also compared among different ages. We found that LPS treated P7, P9, and P14 rat pups had significantly smaller infarct volume compared with saline-treated pups (p ϭ 0.006, 0.03, and 0.01, respectively). This significant reduction in infarct volume was not observed in P3 and P5 rats. TLR-4 expression was significantly higher in older rats compared with P3 and P5 rats (p Ͻ 0.01). These findings indicate that LPS-induced preconditioning is a robust neuroprotective phenomenon in the ischemic developing brain that is age dependent. Pattern of TLR-4 expression is also affected by brain maturity and likely to be responsible for differences in the efficacy of LPS preconditioning. (Pediatr Res 70: 10-14, 2011) D elayed preconditioning is a potent protective phenomenon in which a tissue like the brain develops resistance to ischemic injury after exposure to a variety of subinjurious stimuli such as brief ischemia, hypoxia, or low dose of lipopolysaccharide (LPS) (1-5). This neuroprotective effect is prolonged and can last for several days after the exposure to the subinjurious stimulus. LPS neuroprotection is well documented in adult stroke animal models (6 -9), whereas studies on LPS preconditioning in the hypoxic-ischemic (HI) immature brain are scarce (10,11). In contrast to ischemic adult brain, LPS given to postnatal d 7 (P7) rat pups 72 h before HI injury increased brain damage but was neuroprotective when administered 24 h before the HI insult (10). Recently, we have shown that LPS preconditioning protected against cardiopulmonary bypass-related brain injury in neonatal piglets when administered 72 h before the procedure (11). These conflicting results on the effect of LPS treatment before HI injury in the developing brain may be attributed to differences in LPS doses, time interval between LPS treatment and the severity of the HI insult. Moreover, the influence of brain maturity on the pathophysiology of ischemic injury is well documented (12)(13)(14). It is conceivable, therefore, that there may be a critical developmental window at which the phenomenon of delayed preconditioning can be used to protect the developing brain against ischemic injury.LPS is a known specific ligand for Toll-like receptor 4 (TLR-4), one of the Toll-like receptors (TLRs) that recognize foreign pathogens. LPS-mediated ischemic tolerance in the adult brain occurs by stimulation of TLR-4 signaling pathways (6,15), result...

show abstract

“…Such a comparison between the human and rodent brain will always be arbitrary because of the differences in brain development and anatomy between these species. In human brain development, most neural events occur before birth, whereas in the rat, many of these events occur after birth (15). Also, the rat brain has a lissencephalic surface, whereas the human brain is gyrencephalic.…”

Section: Comparative Aspects Of the P7 Rat Modelmentioning

confidence: 99%

Longitudinal diffusion tensor and manganese-enhanced MRI detect delayed cerebral gray and white matter injury after hypoxia–ischemia and hyperoxia

et al. 2012

View full text Add to dashboard Cite

Background: hypoxia-ischemia (hI) induces delayed inflammation and long-term gray and white matter brain injury that may be altered by hyperoxia. Methods: hI and 2 h of hyperoxia (100% O 2 ) or room air (21% O 2 ) in 7-d-old (P7) rats were studied by magnetic resonance imaging at 7 Tesla during 42 d: apparent diffusion coefficient (aDc) maps on day 1; T 1 -weighted manganese-enhanced images on day 7; diffusion tensor images on days 21 and 42; and T 2 maps at all time points. results: The long-term brain tissue destruction on T 2 maps was more severe in hI+hyperoxia than hI+room air. aDc was lower in hI+hyperoxia vs. hI+room air and sham and was correlated with long-term outcome. Manganese enhancement indicating inflammation was seen in both the groups along with more microglial activation in hI+hyperoxia on day 7. Fractional anisotropy (Fa) in corpus callosum was lower and radial diffusivity was higher in hI+hyperoxia than that in hI+room air and sham on day 21. From day 21 to day 42, Fa and radial diffusivity in hI+hyperoxia were unchanged, whereas in hI+room air, Fa increased and radial diffusivity decreased to values similar to sham. conclusion: hyperoxia caused a more severe tissue destruction, delayed irreversible white matter injury, and increased inflammatory response resulting in a worsening in the trajectory of injury after hI in developing gray and white matter.

show abstract

Animal Models of Perinatal Hypoxic-Ischemic Brain Damage

Cited by 118 publications

References 111 publications

Immediate Hypothermia Is Not Neuroprotective After Severe Hypoxia-Ischemia and Is Deleterious When Delayed by 12 Hours in Neonatal Rats

Immediate Hypothermia Is Not Neuroprotective After Severe Hypoxia-Ischemia and Is Deleterious When Delayed by 12 Hours in Neonatal Rats

Lipopolysaccharide-Induced Preconditioning Against Ischemic Injury Is Associated With Changes in Toll-Like Receptor 4 Expression in the Rat Developing Brain

Longitudinal diffusion tensor and manganese-enhanced MRI detect delayed cerebral gray and white matter injury after hypoxia–ischemia and hyperoxia

Contact Info

Product

Resources

About