Evolution of Brain Injury After Transient Middle Cerebral Artery Occlusion in Neonatal Rats

Derugin, Nikita; Wendland, Michael F.; Muramatsu, Kanji; Roberts, Timothy P. L.; Gregory, George; Ferriero, Donna M.; Vexler, Zinaida S.

doi:10.1161/01.str.31.7.1752

Cited by 106 publications

(104 citation statements)

References 56 publications

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“…ADC values remained stable during the study period in CTL, with values around 1 ϫ 10 Ϫ5 cm 2 /s (23,26,28). In HIϩVEH, ADC evolved from values near 50% of control when measured 24 h after HI, corresponding to a restricted water mobility because of the cytotoxic edema, to supranormal values at P14, corresponding to a mobility near to free water due to cell death (24,26) (Table 1).…”

Section: Resultsmentioning

confidence: 92%

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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Section: Resultsmentioning

confidence: 92%

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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“…Previous reports (9) have shown that there is white matter involvement in neonatal stroke that is difficult to delineate in the neonate using MRI. However, the tfMCAO model appeared to have less corpus callosum involvement than the RVM model (Figs.…”

Section: Discussionmentioning

confidence: 95%

“…Evolution of injury in adult stroke models involving MCAO is described as containing a central primarily necrotic core and potentially salvageable penumbral regions. Imaging of the evolution of such injury is well-described in adult stroke models (16) and more recently in newborns (9,17). Conversion of penumbral regions to irreversible injury is complex and multiple metabolic, inflammatory and apoptotic postreperfusion responses to injury have been described (18).…”

Section: Ischemic Injury In the Rat Pupmentioning

confidence: 99%

Comparison of Two Neonatal Ischemic Injury Models Using Magnetic Resonance Imaging

Ashwal¹,

Tone²,

Tian³

et al. 2007

Pediatr Res

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Using an 11.7-Tesla magnetic resonance imaging (MRI) scanner in 10-d-old rat pups we report on the evolution of injury over 28 d in a model of neonatal stroke (transient filament middle cerebral artery occlusion, tfMCAO) and a model of hypoxicischemic injury (Rice-Vannucci model, RVM). In both models, diffusion-weighted imaging (DWI) was more sensitive in the early detection of ischemia than T2-weighted imaging (T2WI). Injury volumes in both models were greater on d 1 for DWI and d 3 for T2WI, decreased over time and by d 28 T2WI injury volumes (tfMCAO 10.3% of ipsilateral hemisphere; RVM 23.9%) were definable. The distribution of injury with tfMCAO was confined to the vascular territory of the middle cerebral artery and a definable core and penumbra evolved over time. Ischemic injury in the RVM was more generalized and greater in cortical regions. Contralateral hemispheric involvement was only observed in the RVM. Our findings demonstrate that high-field MRI over extended periods of time is possible in a small animal model of neonatal brain injury and that the tfMCAO model should be used for studies of neonatal stroke and that the RVM does not reflect the vascular distribution of injury seen with focal ischemia. (Pediatr Res 61: 9-14, 2007) C urrent neuroprotective therapies of acute stroke in adults have not proven beneficial and because the delay in diagnosis of neonatal stroke is beyond the current window of opportunity for thrombolytic therapy, it is likely that future neonatal care will focus on delayed treatments implemented hours to days after ischemia. Temporally delayed treatment is even more likely in cases of neonatal ischemia as observable signs are more difficult to assess and observe. As such, being able to serially and noninvasively monitor the evolution of neonatal stroke in humans as well as animal models over weeks to months would be advantageous in studying mechanisms of injury, repair and responses to treatment. Magnetic resonance imaging (MRI) has greatly improved our ability to detect stroke in newborns but its use in neonatal stroke models has been limited by the technical challenges in serially acquiring such data (1,2).The current study used high field strength (11.7T; Tesla) MRI to study the evolution of neonatal hypoxic-ischemic injury over a period of 28 d in two different models. We chose to compare a model of neonatal stroke (tfMCAO, transient filament middle cerebral artery occlusion) to that of the more commonly used model of neonatal hypoxic-ischemic brain injury (RVM, Rice-Vannucci model of unilateral carotid ligation and 1.5 h of hypoxia). We hypothesized that MRI could be used in a small animal model to serially and noninvasively monitor the evolution of injury over 28 d and that neuroimaging could elucidate temporal and spatial patterns of injury in the two models. Specifically, we wished to determine whether there were neuroimaging differences between the two models in: (1) the distribution of injury; (2) the degree of injury in striatum and cortex; (3) the evolut...

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“…13,74,78,79 Figure 1B shows that diffusion-weighted MRI depicts expansion of tissue 'at risk' associated with longer MCAO duration. Other MRI modalities have been proven useful in determining the extent of microcirculatory disturbances during MCAO and after reperfusion (perfusion-sensitive MRI), 76 disruption of the blood-brain barrier (BBB) (Gd-enhanced T1W imaging), 76 elucidation of the evolving injury (T2W imaging), 56,73,80 and changes in brain connectivity after injury during the neonatal period (diffusion tensor imaging). 81 Studies in tMCAO and H-I models in neonatal rodents have shown that although the components of injury that induce cell death and brain injury are similar to those occurring in experimental models of preterm injury-excitotoxic, oxidant, and inflammatory components-the targeted cell populations and regions affected by cerebral hypoxia and ischemia are different.…”

Section: Animal Models and The Underlying Mechanisms Of Perinatal Artmentioning

confidence: 99%

Mechanisms of Perinatal Arterial Ischemic Stroke

Fernández-López

Natarajan

Ashwal

et al. 2014

J Cereb Blood Flow Metab

108

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The incidence of perinatal stroke is high, similar to that in the elderly, and produces a significant morbidity and severe long-term neurologic and cognitive deficits, including cerebral palsy, epilepsy, neuropsychological impairments, and behavioral disorders. Emerging clinical data and data from experimental models of cerebral ischemia in neonatal rodents have shown that the pathophysiology of perinatal brain damage is multifactorial. These studies have revealed that, far from just being a smaller version of the adult brain, the neonatal brain is unique with a very particular and age-dependent responsiveness to hypoxia-ischemia and focal arterial stroke. In this review, we discuss fundamental clinical aspects of perinatal stroke as well as some of the most recent and relevant findings regarding the susceptibility of specific brain cell populations to injury, the dynamics and the mechanisms of neuronal cell death in injured neonates, the responses of neonatal blood-brain barrier to stroke in relation to systemic and local inflammation, and the long-term effects of stroke on angiogenesis and neurogenesis. Finally, we address translational strategies currently being considered for neonatal stroke as well as treatments that might effectively enhance repair later after injury.

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Evolution of Brain Injury After Transient Middle Cerebral Artery Occlusion in Neonatal Rats

Cited by 106 publications

References 56 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

Comparison of Two Neonatal Ischemic Injury Models Using Magnetic Resonance Imaging

Mechanisms of Perinatal Arterial Ischemic Stroke

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