Resuscitative Hypothermia Protects the Neonatal Rat Brain from Hypoxic‐Ischemic Injury

Nedelcu, Johann; Klein, Michael A.; Aguzzi, Adriano; Martin, Ernst

doi:10.1111/j.1750-3639.2000.tb00243.x

Cited by 52 publications

(27 citation statements)

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“…Some of these reports have described a reduction by 42%-65% of the injured area when using hypothermia as neuroprotective strategy (30,31), a proportion very similar to that obtained with WIN. In addition, WIN reduced the shrinkage of the ipsilateral hemisphere observed after HI.…”

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confidence: 90%

The Cannabinoid Agonist Win55212 Reduces Brain Damage in an In Vivo Model of Hypoxic-Ischemic Encephalopathy in Newborn Rats

et al. 2007

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Neonatal hypoxic-ischemic encephalopathy (NHIE) is a devastating condition for which effective therapeutic treatments are still unavailable. Cannabinoids emerge as neuroprotective substances in adult animal studies; therefore, we aimed herein to test whether cannabinoids might reduce brain damage induced by hypoxiaischemia (HI) in newborn rats. Thus, 7-d-old Wistar rats (P7) were exposed to 8% O 2 for 120 min after left carotid artery ligature, then received s.c. vehicle (VEH) (HIϩVEH), the cannabinoid agonist WIN55212 (WIN) (0.1 mg/kg), or WIN with the CB 1 or CB 2 receptor antagonist SR141617 (SR1) (3 mg/kg) or SR141588 (SR2) (2 mg/kg). Brain damage was assessed by magnetic resonance imaging (MRI) at 1, 3, and 7 d after the insult. At the end of the experiment, MRI findings were corroborated by histology (Nissl staining). HIϩVEH showed an area of cytotoxic and vasogenic edema at 24 h after the insult, then evolving to necrosis. HIϩWIN showed a similar damaged area at 24 h after the insult, but the final necrotic area was reduced by 66%. Coadministration of either SR1 or SR2 reversed the effects of WIN. N HIE remains as a prevalent condition, inducing devastating brain injury leading to death or long-lasting sequelae (1,2). Despite recent progress in neonatology, the incidence of NHIE is not decreasing, likely because the complex pathophysiology of NHIE demands combined therapies or the use of treatments acting at different levels, as hypothermia (1,(3)(4)(5). In addition, due to the current inability to predict accurately perinatal asphyxia, only a posteriori treatments are feasible (1,2).Cannabinoids and their receptors constitute an endogenous system involved, for instance, in the control of synaptic transmission, memory modulation, motivation, movement, nociception, appetite, and thermoregulation (6,7). Two cannabinoid receptors present in the brain have been cloned so far: CB 1 receptors are expressed primarily by neurons but can also be found in glial cells; CB 1 receptors are Gi/o proteincoupled receptors that modulate the activity of several plasma membrane proteins and intracellular signaling pathways (7,8). CB 2 receptors are also Gi/o protein-coupled receptors; although it is accepted that CB 2 receptors are not expressed in forebrain neurons, they have been described in activated glia (8 -10). Lately, cannabinoids are emerging as valuable neuroprotective agents in models of acute and chronic neurodegenerative conditions (6,7,11-15), which may also affect the immature rat brain (16).Due to this evidence, we decided to test whether cannabinoids might be useful for decreasing brain damage in NHIE. For this purpose, we used the Rice-Vannucci model (17), an in vivo model that closely mimics actual NHIE conditions. Importantly, we assessed the effect of WIN when administered after the onset of the HI insult. To evaluate brain damage, we used MRI, an approach with several advantages: (1) MRI allows the development of imaging-based longitudinal studies, providing important data on the response tim...

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The Cannabinoid Agonist Win55212 Reduces Brain Damage in an In Vivo Model of Hypoxic-Ischemic Encephalopathy in Newborn Rats

et al. 2007

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“…However, in neonates with severe HIE, little neuroprotection could be achieved using current HT protocols in which whole-body or head cooling is performed for 48 to 72 h by maintaining the core temperature within a range of 33.5 to 34.5°C (2)(3)(4)(5). In animal studies, the efficacy of postischemic HT was also limited in the subgroup with severe ischemic injury (6,7). To treat severe HIE by HT, a recent review suggested a "deeper" and "more prolonged" cooling (8).…”

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confidence: 99%

Long-Term Neuroprotective Effect of Postischemic Hypothermia in a Neonatal Rat Model of Severe Hypoxic Ischemic Encephalopathy: A Comparative Study on the Duration and Depth of Hypothermia

2010

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ABSTRACT:It is not known whether deeper or longer hypothermia (HT) can achieve better neuroprotection against hypoxic ischemic encephalopathy (HIE) in neonates. To compare the neuroprotective effects of different durations and temperatures of postischemic HT in neonatal rats with severe HIE, 7-d-old rats were subjected to the Rice-Vannucci model for 150 min hypoxia. Only the rats with identified brain lesions in diffusion-weighted MRI were assigned to normothermia (NT, 36°C/48 h) or four HT (HT-30°C/48 h; HT-30°C/24 h; HT-33°C/48 h; and HT-33°C/24 h) groups.1 H-magnetic resonance spectroscopy ( 1 H-MRS) and T2-weighted MRI were obtained serially, and functional studies were performed. HT groups showed significantly greater residual hemispheric volume and better rotarod and cylinder tests than did the NT group at 5 wk postischemia. HT groups also showed lower lactate-plus-lipid level in 1 H-MRS than did the NT group at 7 d postischemia. All of these outcome variables, however, did not differ among the 4 HT subgroups, despite a trend toward greater residual brain volume in the 48-h HT versus 24-h HT subgroups. In conclusion, neither reducing the target temperature from 33 to 30°C nor prolonging the duration from 24 to 48 h produced further improvements in neurologic outcomes in neonatal rat with HIE. (Pediatr Res 68: 303-308, 2010) H ypothermia (HT) is one of the most promising neuroprotective modalities against hypoxic ischemic encephalopathy (HIE) in neonatal brain (1). However, in neonates with severe HIE, little neuroprotection could be achieved using current HT protocols in which whole-body or head cooling is performed for 48 to 72 h by maintaining the core temperature within a range of 33.5 to 34.5°C (2-5). In animal studies, the efficacy of postischemic HT was also limited in the subgroup with severe ischemic injury (6,7). To treat severe HIE by HT, a recent review suggested a "deeper" and "more prolonged" cooling (8). However, no controlled clinical trials have tested this supposition and several experimental studies failed to clearly demonstrate an effect of postischemic HT protocols with different target temperatures or duration in a perinatal HIE model (9 -11).The 7-d-old rat with unilateral carotid artery ligation and subsequent exposure to 8% hypoxia is the most commonly used model to evaluate the efficacy of therapeutic interventions in the developing brain (12), and several studies have used this Rice-Vannucci model (RVM) to test the effects of HT (10,11,(13)(14)(15)(16)(17)(18)(19). However, an experimental design composed of a shorter duration of hypoxia, representing "mild" ischemic lesions, is not appropriate for evaluating the neuroprotective effect of HT against severe HIE. To date, few experimental studies have used the RVM with hypoxia exposure longer than 120 min (10,13,19), but none of these have reported the long-term neuroprotective effect of postischemic HT.The aim of this study was to investigate the long-term neuroprotective effect of various postischemic HT protocols with different t...

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“…10 In an animal study, hypothermia was also demonstrated to have protective effects in mild but not in severe hypoxia-ischemia. 11 Therefore, it is also useful to identify a noninvasive method to detect and monitor the evolution of HI-induced WM damage for treatment selection and to determine the effectiveness of treatment.…”

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Mild Hypoxic-Ischemic Injury in the Neonatal Rat Brain: Longitudinal Evaluation of White Matter Using Diffusion Tensor MR Imaging

Wang

Wu²,

Cai³

et al. 2009

AJNR Am J Neuroradiol

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Resuscitative Hypothermia Protects the Neonatal Rat Brain from Hypoxic‐Ischemic Injury

Cited by 52 publications

References 47 publications

The Cannabinoid Agonist Win55212 Reduces Brain Damage in an In Vivo Model of Hypoxic-Ischemic Encephalopathy in Newborn Rats

The Cannabinoid Agonist Win55212 Reduces Brain Damage in an In Vivo Model of Hypoxic-Ischemic Encephalopathy in Newborn Rats

Long-Term Neuroprotective Effect of Postischemic Hypothermia in a Neonatal Rat Model of Severe Hypoxic Ischemic Encephalopathy: A Comparative Study on the Duration and Depth of Hypothermia

Mild Hypoxic-Ischemic Injury in the Neonatal Rat Brain: Longitudinal Evaluation of White Matter Using Diffusion Tensor MR Imaging

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