A new model of white matter injury in neonatal rats with bilateral carotid artery occlusion

Uehara, Hisakazu; Yoshioka, Hiroshi; Kawase, Shoji; Nagai, Hideyuki; Ohmae, Tadaki; Hasegawa, Kou; Sawada, Tadashi

doi:10.1016/s0006-8993(99)01675-3

Cited by 74 publications

(52 citation statements)

References 24 publications

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“…APP, a membrane spanning glycoprotein, is normally produced in the neuronal cell body and quickly carried along the axon through fast anterograde axonal transport (Deguchi et al, 1999;Meng et al, 1997;Sheriff et al, 1994). The amount of APP in normal axons and neurons is not enough to be detected, but the accumulation of APP can be visualized in human and animal brain with lesions (Deguchi et al, 1999;Meng et al, 1997;Uehara et al, 1999). APP has been detected as an early sign of axonal and neuronal lesions in prenatal-onset PVL, but is not detectable in the late stage of prenatal PVL (Deguchi et al, 1999;Meng et al, 1997;Uehara et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The amount of APP in normal axons and neurons is not enough to be detected, but the accumulation of APP can be visualized in human and animal brain with lesions (Deguchi et al, 1999;Meng et al, 1997;Uehara et al, 1999). APP has been detected as an early sign of axonal and neuronal lesions in prenatal-onset PVL, but is not detectable in the late stage of prenatal PVL (Deguchi et al, 1999;Meng et al, 1997;Uehara et al, 1999). LPS exposure also resulted in the reduced length and the increased width of the MAP1 immunostained axons in the fifth layer of parietal cortex in the P8 rat brain (Fig 3B) and the enlarged nuclear size of neurons in this area ( Fig 3E).…”

Section: Discussionmentioning

confidence: 99%

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α-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain

et al. 2008

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Although white matter damage is a fundamental neuropathological feature of periventricular leukomalacia (PVL), the motor and cognitive deficits observed later in infants with PVL indicate the possible involvement of cerebral neuronal dysfunction. Using a previously developed rat model of white matter injury induced by cerebral lipopolysaccharide (LPS) injection, we investigated whether LPS exposure also results in neuronal injury in the neonatal brain and whether α-phenyl-n-tert-butylnitrone (PBN), an antioxidant, offers protection against LPS-induced neuronal injury. A stereotactic intracerebral injection of LPS (1 mg/kg) was performed in Sprague-Dawley rats (postnatal day 5) and control rats were injected with sterile saline. LPS exposure resulted in axonal and neuronal injury in the cerebral cortex as indicated by elevated expression of β-amyloid precursor protein, altered axonal length and width, and increased size of cortical neuronal nuclei. LPS exposure also caused loss of tyrosine hydroxylase positive neurons in the substantia nigra and the ventral tegmental areas of the rat brain. Treatments with PBN (100 mg/kg) significantly reduced LPS-induced neuronal and axonal damage. The protection of PBN was associated with an attenuation of oxidative stress induced by LPS as indicated by the reduced number of 4-hydroxynonenal, malondialdehyde or nitrotyrosine positive cells in the cortical area following LPS exposure, and with the reduction in microglial activation stimulated by LPS. The finding that an inflammatory environment may cause both white matter and neuronal injury in the neonatal brain supports the possible anatomical correlate for the intellectual deficits and the other cortical and deep gray neuronal dysfunctions associated with PVL. The protection of PBN may indicate the potential usefulness of antioxidants for treatment of these neuronal dysfunctions.Keywords neuronal injury; tyrosine hydroxylase; microglial activation; oxidative stress; antioxidant Periventricular leukomalacia (PVL), the dominant form of brain injury in the preterm infant, is frequently associated with subsequent adverse neurological outcomes such as cerebral palsy and mental retardation (Rezaie and Dean, 2002;Volpe, 2003). Although white matter damage is a fundamental neuropathological feature of PVL, the motor and cognitive deficits observed later in these infants indicate possible cerebral cortical neuronal dysfunction. The precise nature Corresponding author: Dr. Zhengwei Cai Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216-4504, USA Tel.: +1-601-984-2786 Fax: +1-601-815-3666 E-mail address: zcai@ped.umsmed.edu (Z. Cai). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Pleas...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

α-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain

et al. 2008

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“…The fetal sheep cerebrum has a predilection for relatively selective WMI under conditions of moderate cerebral ischemia [41], whereas rodents have a propensity for mixed cerebral injury such that substantial gray matter injury accompanies WMI [47][48][49][50][51][52]. This shortcoming, for example, limits the relevance of rodent hypoxia-ischemia models for the study of myelination disturbances associated with chronic human WMI.…”

Section: Advantages and Disadvantages Of The Fetal Sheep To Model Wmimentioning

confidence: 99%

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

et al. 2012

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Despite advances in neonatal intensive care, survivors of premature birth remain highly susceptible to unique patterns of developmental brain injury that manifest as cerebral palsy and cognitive-learning disabilities. The developing brain is particularly susceptible to cerebral white matter injury related to hypoxia-ischemia. Cerebral white matter development in fetal sheep shares many anatomical and physiological similarities with humans. Thus, the fetal sheep has provided unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in models that replicate major features of acute and chronic human cerebral injury and have provided access to complex clinically relevant studies of cerebral blood flow and neuroimaging that are not feasible in smaller laboratory animals. Here, we focus on emerging insights and methodologies from studies in fetal sheep that have begun to define cellular and vascular factors that contribute to white matter injury. Recent advances include spatially defined measurements of cerebral blood flow in utero, the definition of cellular maturational factors that define the topography of injury and the application of high-field magnetic resonance imaging to define novel neuroimaging signatures for specific types of chronic white matter injury. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they provide powerful access to clinically relevant studies that provide a more integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

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“…The operation was conducted as previously described with slight modification 30,31 . The rats were anaesthetized with ketamine 60 mg/kg and xylazine 6 mg/kg intramuscularly.…”

Section: Surgical Proceduresmentioning

confidence: 99%

Ceftriaxone improves spatial learning and memory in chronic cerebral hypoperfused rats

Koomhin¹,

Tilokskulchai²,

Tapechum

2012

ScienceAsia

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Cerebral hypoperfusion is associated with cognitive decline in ageing, mild cognitive impairment, vascular type dementia, and Alzheimer's disease. The mechanisms leading to such neurological impairments are still uncertain. Although several mechanisms have been proposed as contributing factors leading to neuronal injury, glutamate excitotoxicity seems to be the relevant one. Recently, it was found that β-lactam antibiotics such as ceftriaxone show a neuroprotective effect by upregulation of glutamate transporter and reduction of glutamate excitotoxicity. To study the contribution of glutamate excitotoxicity and the effects of ceftriaxone on spatial learning and memory in chronic cerebral hypoperfusion, we conducted experiments in rats subjected to permanent bilateral common carotid artery occlusion. Ceftriaxone (200 mg/kg) was injected daily in rats for 5 days after the onset of the arterial ligation. A Morris water maze was used to assess learning and memory two months after arterial ligation. Hippocampal histology and glutamate transporter 1 (GLT-1) expression were also studied. Results showed that ceftriaxone improved learning and memory performance. Consistently, the histological study showed an increase hippocampal CA1 and CA3 neuronal numbers in the ceftriaxone-treated group compared with the vehicle-treated group. Although not statistically significant, the GLT-1 protein level in the hippocampus was 86% higher than the sham group. We conclude that ceftriaxone treatment can attenuate neuronal injury and improve spatial learning and memory after chronic cerebral hypoperfusion and that glutamate excitotoxicity may play an important role in the pathophysiology of chronic cerebral hypoperfusion.

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A new model of white matter injury in neonatal rats with bilateral carotid artery occlusion

Cited by 74 publications

References 24 publications

α-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain

α-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

Ceftriaxone improves spatial learning and memory in chronic cerebral hypoperfused rats

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