Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role for Topiramate

Follett, Pamela L.; Deng, Wenbin; Dai, Weimin; Talos, Delia M.; Massillon, Leon; Rosenberg, Paul A.; Volpe, Joseph J.; Jensen, Frances E.

doi:10.1523/jneurosci.0477-04.2004

Cited by 291 publications

(295 citation statements)

References 55 publications

(97 reference statements)

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“…We have shown that white matter and developing OLs are vulnerable to HI insult at P6 in our rat model of PVL (23,24). As previously described, the majority of OLs at P6 in the periventricular white matter and cortex are O4 and O1 positive and not myelin basic protein (MBP) expressing (21,25).…”

Section: Nkcc1 Is Expressed On Developing Ols and Neurons In The Immasupporting

confidence: 69%

Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia

Jantzie

Park

et al. 2015

Pediatr Res

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Background: Periventricular leukomalacia (PVL) is a major form of preterm brain injury. Na + -K + -Cl − 1 cotransporter (NKCC1) expression on neurons and astrocytes is developmentally regulated and mediates Cl − reversal potential. We hypothesized that NKCC1 is highly expressed on oligodendrocytes (OLs) and increases vulnerability to hypoxia-ischemia (HI) mediated white matter injury, and that the NKCC1 inhibitor bumetanide would be protective in a rodent PVL model. Methods: Immunohistochemistry in Long-Evans rats and PLP-EGFP transgenic mice was used to establish cell-specific expression of NKCC1 in the immature rodent brain. HI was induced on postnatal day 6 (P6) in rats and the protective efficacy of bumetanide (0.3 mg/kg/i.p. q12h × 60 h) established. results: NKCC1 was expressed on OLs and subplate neurons through the first 2 postnatal weeks, peaking in white matter and the subplate between P3-7. Following HI, NKCC1 is expressed on OLs and neurons. Bumetanide treatment significantly attenuates myelin basic protein loss and neuronal degeneration 7 d post-HI. conclusion: Presence and relative overexpression of NKCC1 in rodent cerebral cortex coincides with a period of developmental vulnerability to HI white matter injury in the immature prenatal brain. The protective efficacy of bumetanide in this model of preterm brain injury suggests that Cl − transport is a factor in PVL and that its inhibition may have clinical application in premature human infants.

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Section: Nkcc1 Is Expressed On Developing Ols and Neurons In The Immasupporting

confidence: 69%

Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia

Jantzie

Park

et al. 2015

Pediatr Res

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“…In animal models of cerebral ischemia, TPM reduced the severity of cerebral damage either alone [5][6][7][8] or with hypothermia. 9 The neuroprotective mechanisms of TPM action appear related not only to glutamate a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors inhibition, 11,[27][28][29][30] but also to inhibition of Na + channels, 31 high voltageactivated calcium currents, 4 carbonic anhydrase isoenzymes, 32 and mitochondrial permeability transition pore. 19 Hypothermia, conversely, might enhance post-ischemic glutamate reuptake 33 , and suppress nitric oxide synthase, oxidative stress, apoptosis, and inflammatory cascades.…”

Section: Resultsmentioning

confidence: 99%

“…TPM has neuroprotective properties against hypoxic ischemic brain damage, both in vitro and in animal models, and was included in neuroprotective strategies for ischemic stroke [4][5][6][7][8][9][10][11] and neonatal hypoxic-ischemic cerebral injury. 12 Several studies have demonstrated the therapeutic effects of whole-body or selective head cooling to treat asphyxiated newborns.…”

mentioning

confidence: 99%

Oral Topiramate in Neonates with Hypoxic Ischemic Encephalopathy Treated with Hypothermia: A Safety Study

Filippi

Poggi

Marca

et al. 2010

The Journal of Pediatrics

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Objective To investigate whether topiramate associated with mild or deep hypothermia in asphyxiated term infants is safe in relation to the short-term outcome.Study design We report on 27 consecutive asphyxiated newborns who were treated with whole body hypothermia and 27 additional consecutive newborns with hypothermia who were co-treated with oral topiramate, once a day for 3 consecutive days, at 2 different doses.Results Newborns were divided in 6 groups according to the depth of hypothermia and the association with higher or lower topiramate dosage. A statistical comparison of the groups identified some differences in biochemical and hemodynamic variables, but no adverse effects attributable to topiramate were detected. There were no statistically significant differences in the groups in short-term outcomes, survival rate at discharge, or incidence of pathologic brain magnetic resonance imaging. ConclusionAlthough the number of newborns in this study was limited, the short-term outcome and the safety data appear to support the evaluation of topiramate in clinical trials to explore its possible additive neuroprotective action. (J Pediatr 2010;157:361-6).See editorial, p 351 and related articles, p 367 and p 499 N eonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is one of the leading causes of cerebral palsy, the incidence of which has remained essentially unchanged in recent decades despite improvements in perinatal practice and neonatal care.1 Topiramate (TPM), an anticonvulsant agent widely used in adults and children, 2,3 has multiple mechanisms of action, including an inhibitory effect on glutamate receptors. TPM has neuroprotective properties against hypoxic ischemic brain damage, both in vitro and in animal models, and was included in neuroprotective strategies for ischemic stroke 4-11 and neonatal hypoxic-ischemic cerebral injury. 12Several studies have demonstrated the therapeutic effects of whole-body or selective head cooling to treat asphyxiated newborns. [13][14][15] Consequently, mild hypothermia is recommended for the treatment of moderate degrees of encephalopathy. 1 Deep hypothermia may also be safe and neuroprotective. 16 Although TPM logically would be expected to enhance the neuroprotective effects of hypothermia in HIE, no trial has tested this combination treatment.1 Hypothermia can reduce drug clearance, thereby affecting the pharmacokinetics of drugs. 17 In an earlier pilot study, we assessed the effects of mild or deep hypothermia on TPM pharmacokinetics in neonates with HIE. We observed a slow absorption and elimination of TPM. 18 We now report the safety profile of TPM in neonates treated with hypothermia in a retrospective comparison with newborns treated with hypothermia only. MethodsWe studied asphyxiated newborns admitted in 2 neonatal intensive care units

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“…A hypoxic/ischemic model of PVL in the rat at P7 has been previously established 3 . This model is unique in that it resembles PVL in premature infants.…”

Section: Discussionmentioning

confidence: 99%

Mouse Models of Periventricular Leukomalacia

Shen¹,

Plane²,

Deng³

2010

JoVE

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We describe a protocol for establishing mouse models of periventricular leukomalacia (PVL). PVL is the predominant form of brain injury in premature infants and the most common antecedent of cerebral palsy. PVL is characterized by periventricular white matter damage with prominent oligodendroglial injury. Hypoxia/ischemia with or without systemic infection/inflammation are the primary causes of PVL. We use P6 mice to create models of neonatal brain injury by the induction of hypoxia/ischemia with or without systemic infection/inflammation with unilateral carotid ligation followed by exposure to hypoxia with or without injection of the endotoxin lipopolysaccharide (LPS). Immunohistochemistry of myelin basic protein (MBP) or O1 and electron microscopic examination show prominent myelin loss in cerebral white matter with additional damage to the hippocampus and thalamus. Establishment of mouse models of PVL will greatly facilitate the study of disease pathogenesis using available transgenic mouse strains, conduction of drug trials in a relatively high throughput manner to identify candidate therapeutic agents, and testing of stem cell transplantation using immunodeficiency mouse strains. Video LinkThe video component of this article can be found at http://www.jove.com/video/1951/ ProtocolDetailed procedures of creating neonatal brain injury in P6 mice:1. Postnatal day 6 (P6) mice are anesthetized with indirect cooling on ice to the point of unresponsiveness to noxious stimulation (deep anesthesia). 2. Following cleaning the skin with alcohol, a midline ventral incision is made in the anterior neck. 3. Under a dissecting microscope, the bifurcation of the right common carotid artery is approached by gently retracting the omohyoid and sternocleidomastoid muscles. 4. The fascia around the carotid sheath is removed, and the proximal internal branch isolated from the nearby vagus nerve and sympathetic ganglia with a hook. The internal carotid artery is then cauterized using a cauterizing tip. 5. Following cauterization, the skin incision is sutured, and the animal is kept warm until fully awake and then returned to the dam. 6. One hour after ligation, the animal is placed in a sealed chamber infused with nitrogen until a level of 6.0% O 2 is reached. The animal is then exposed to 35 min of hypoxia. 7. After hypoxia exposure, the mouse recovers on a heating pad (33°C) for 30 min and then is returned to the dam. For creation of brain injury with combined hypoxia/ischemia and infection/inflammation, the animal is then injected intraperitoneally with 0.015 ml of lipopolysaccharide (LPS, 1 mg/kg). 8. Four days post-hypoxia/ischemia, mice are anesthetized with indirect cooling on ice to the point of unresponsiveness to noxious stimuli, then perfused with saline and then 4% paraformaldehyde. Brains are removed and cryoprotected.

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Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role for Topiramate

Cited by 291 publications

References 55 publications

Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia

Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia

Oral Topiramate in Neonates with Hypoxic Ischemic Encephalopathy Treated with Hypothermia: A Safety Study

Mouse Models of Periventricular Leukomalacia

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