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Steven W. Levison - One of the best experts on this subject based on the ideXlab platform.
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moderately inducing autophagy reduces tertiary brain injury after Perinatal Hypoxia ischemia
Cells, 2021Co-Authors: Brian H Kim, Maciej Jeziorek, Hur Dolunay Kanal, Viorica Raluca Contu, Radek Dobrowolski, Steven W. LevisonAbstract:Recent studies of cerebral Hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)β1 is highly elevated following HI and that delivering an antagonist for TGFβ receptor activin-like kinase 5 (ALK5)—SB505124—three days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated light chain 3 (LC3), a key protein known to mediate autophagy. However, those studies did not determine whether (1) SB was acting directly on the CNS and (2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist three days after HI reduced actively apoptotic cells by ~90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting three days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial.
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moderately inducing autophagy reduces tertiary brain injury after Perinatal Hypoxia ischemia
bioRxiv, 2020Co-Authors: Brian H Kim, Maciej Jeziorek, Hur Dolunay Kanal, Radek Dobrowolski, Steven W. LevisonAbstract:Recent studies of cerebral Hypoxia-ischemia (HI) have highlighted slowly progressive neurodegeneration whose mechanisms remain elusive, but if blocked, could considerably improve long-term neurological function. We previously established that the cytokine transforming growth factor (TGF)β1 is highly elevated following HI and that delivering an antagonist for TGFβ receptor activin-like kinase 5 (ALK5) -SB505124 - 3 days after injury in a rat model of moderate pre-term HI significantly preserved the structural integrity of the thalamus and hippocampus as well as neurological functions associated with those brain structures. To elucidate the mechanism whereby ALK5 inhibition reduces cell death, we assessed levels of autophagy markers in neurons and found that SB505124 increased numbers of autophagosomes and levels of lipidated LC3 (light chain 3), a key protein known to mediate autophagy. However, those studies did not determine whether 1) SB was acting directly on the CNS and 2) whether directly inducing autophagy could decrease cell death and improve outcome. Here we show that administering an ALK5 antagonist 3 days after HI reduced actively apoptotic cells by ~90% when assessed one week after injury. Ex vivo studies using the lysosomal inhibitor chloroquine confirmed that SB505124 enhanced autophagy flux in the injured hemisphere, with a significant accumulation of the autophagic proteins LC3 and p62 in SB505124 + chloroquine treated brain slices. We independently activated autophagy using the stimulatory peptide Tat-Beclin1 to determine if enhanced autophagy is directly responsible for improved outcomes. Administering Tat-Beclin1 starting 3 days after injury preserved the structural integrity of the hippocampus and thalamus with improved sensorimotor function. These data support the conclusion that intervening at this phase of injury represents a window of opportunity where stimulating autophagy is beneficial.
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death effector activation in the subventricular zone subsequent to Perinatal Hypoxia ischemia
Journal of Neurochemistry, 2007Co-Authors: Michael J. Romanko, Steven W. Levison, Changlian Zhu, Klas Blomgren, Ben A BahrAbstract:Perinatal Hypoxia/ischemia (H/I) is the leading cause of neurological injury resulting from birth complications and pre-maturity. Our studies have demonstrated that this injury depletes the subventricular zone (SVZ) of progenitors. In this study, we sought to reveal which cell death pathways are activated within these progenitors after H/I. We found that calpain activity is detected as early as 4 h of reperfusion and is sustained for 48 h, while caspase 3 activation does not occur until 8 h and peaks at 24 h post-insult. Activated calpains and caspase 3 co-localized within precursors situated in the lateral aspects of the SVZ (which coincides with progenitor cell death), whereas neither enzyme was activated in the medial SVZ (which harbors the neural stem cells that are resilient to this insult). These studies reveal targets for neuroprotective agents to protect precursors from cell death towards the goal of restoring normal brain development after H/I.
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leukemia inhibitory factor participates in the expansion of neural stem progenitors after Perinatal Hypoxia ischemia
Neuroscience, 2007Co-Authors: Matthew V Covey, Steven W. LevisonAbstract:Subsequent to Perinatal Hypoxia/ischemia there is an increase in the number of neural stem/progenitor cells (NSP) within the subventricular zone (SVZ). Gene expression analyses have implicated Notch signaling in the expansion of these tripotential cells but there are limited data as to which signals are stimulating Notch activation. There is evidence that the leukemia inhibitory factor receptor (LIFR)/gp130 receptor heterodimer induces Notch1 to maintain NSP populations during normal development. LIF and ciliary neurotrophic factor (CNTF) bind to these receptor components and they coordinate injury responses in the CNS. Therefore, the aim of these studies was to investigate whether CNTF and/or leukemia inhibitory factor (LIF) participate in NSP expansion in the rat SVZ after Hypoxia/ischemia (H/I) as well as to characterize the downstream events that regulate NSP numbers. We report that LIF mRNA is induced 48 h post-insult by 13-fold but that it returns almost to baseline by 72 h. Commensurate with increased LIF expression there is a corresponding increase in phosphorylated Stat-3 within the SVZ. Modeling the changes that occur in vivo, we show that LIF induces Stat-3 phosphorylation in neurospheres to enhance Delta-like-1 and Notch1 expression as well as to increase Notch1 activation. LIF also expands neurosphere number and size in vitro. Whereas CNTF can mimic the effects of LIF in vitro, CNTF expression in the SVZ was unchanged during recovery from H/I. Cumulatively, these data implicate LIF and not CNTF in the expansion of NSPs in the rat SVZ after Perinatal brain injury. As both LIF expression and the endogenous regenerative response after brain injury are time-delimited, these findings provide insights into strategies to expand the endogenous pool of NSPs to repopulate the damaged brain.
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neural stem progenitor cells participate in the regenerative response to Perinatal Hypoxia ischemia
The Journal of Neuroscience, 2006Co-Authors: Ryan J. Felling, Matthew J. Snyder, Michael J. Romanko, Raymond P. Rothstein, Amber N. Ziegler, Zhengang Yang, Maria I. Givogri, Ernesto R. Bongarzone, Steven W. LevisonAbstract:Perinatal Hypoxia/ischemia (H/I) is the leading cause of neurologic injury resulting from birth complications. Recent advances in critical care have dramatically improved the survival rate of infants suffering this insult, but ∼50% of survivors will develop neurologic sequelae such as cerebral palsy, epilepsy or cognitive deficits. Here we demonstrate that tripotential neural stem/progenitor cells (NSPs) participate in the regenerative response to Perinatal H/I as their numbers increase 100% by 3 d and that they alter their intrinsic properties to divide using expansive symmetrical cell divisions. We further show that production of new striatal neurons follows the expansion of NSPs. Increased proliferation within the NSP niche occurs at 2 d after Perinatal H/I, and the proliferating cells express nestin. Of those stem-cell related genes that change, the membrane receptors Notch1, gp-130, and the epidermal growth factor receptor, as well as the downstream transcription factor Hes5, which stimulate NSP proliferation and regulate stem cellness are induced before NSP expansion. The mechanisms for the reactive expansion of the NSPs reported here reveal potential therapeutic targets that could be exploited to amplify this response, thus enabling endogenous precursors to restore a normal pattern of brain development after Perinatal H/I.
Donna M Ferriero - One of the best experts on this subject based on the ideXlab platform.
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copper zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after Perinatal Hypoxia ischemia
Annals of Neurology, 1998Co-Authors: Heather J Fullerton, Jeremy S Ditelberg, Charles J Epstein, Donna M Ferriero, Sylvia F Chen, Dean P Sarco, Pak H ChanAbstract:Unlike the mature animal, immature mice transgenic for copper/zinc superoxide dismutase (SODI) have greater brain injury after Hypoxia-ischemia than their wild-type nontransgenic littermates. To assess the role of oxidative stress in the pathogenesis of this injury, we measured histopathological damage, lipid peroxidation products, enzymatic activities of catalase and glutathione peroxidase, and hydrogen peroxide (H 2 O 2 ) concentration in these animals before and after hypoxic-ischemic injury. Lipid peroxidation products were significantly increased 2 hours after the insult in both transgenic and nontransgenic brains in hippocampus, the most damaged brain region. Catalase activity did not increase in response to SOD1 overexpression or injury in either group. However, glutathione peroxidase activity, unchanged in response to overexpression, decreased significantly 24 hours after injury in both groups. At 24 hours after injury, greater H 2 O 2 accumulation was observed in transgenic brains. Because SOD1 dismutates superoxide to H 2 O 2 , overexpression of SOD1 in the presence of developmentally low activities of the catalytic enzymes glutathione peroxidase and catalase leads to an increased production of H 2 O 2 , and may explain the increased brain injury observed after Hypoxia-ischemia in neonatal SOD1 mice.
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brain injury after Perinatal Hypoxia ischemia is exacerbated in copper zinc superoxide dismutase transgenic mice
Pediatric Research, 1996Co-Authors: Jeremy S Ditelberg, Ann R Sheldon, Charles J Epstein, Donna M FerrieroAbstract:The role of superoxide radical formation in the pathogenesis of Perinatal hypoxic-ischemic injury was examined using transgenic (Tg) mice expressing three times normal amounts of copper/zinc-superoxide dismutase (CuZn/SOD). Fourteen litters of postnatal d 7 strain 218/3 mice were subjected to right common carotid artery ligation followed by 90 min of Hypoxia in an 8% oxygen/humidified chamber maintained at 37°C. Both Tg mice (n = 32) and their nontransgenic (nTg) littermates (n = 30) survived the injury equally. Evaluation of infarcted brain areas measured by video image analysis of three coronal brain sections through the anterior hippocampus from each animal revealed that the Tg animals suffered brain infarction more frequently than did nTg mice. Blinded histologic scoring of cerebral cortex and striatum 5 d after injury revealed that Tg mice were more likely to have higher histologic severity scores than their nTg littermates (p = 0.0463, Mann-Whitney U test). These findings suggest that brain injury in Perinatal Hypoxia-ischemia may be mediated in part by free radical formation from excessive hydrogen peroxide or nitric oxide production.
Jeremy S Ditelberg - One of the best experts on this subject based on the ideXlab platform.
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copper zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after Perinatal Hypoxia ischemia
Annals of Neurology, 1998Co-Authors: Heather J Fullerton, Jeremy S Ditelberg, Charles J Epstein, Donna M Ferriero, Sylvia F Chen, Dean P Sarco, Pak H ChanAbstract:Unlike the mature animal, immature mice transgenic for copper/zinc superoxide dismutase (SODI) have greater brain injury after Hypoxia-ischemia than their wild-type nontransgenic littermates. To assess the role of oxidative stress in the pathogenesis of this injury, we measured histopathological damage, lipid peroxidation products, enzymatic activities of catalase and glutathione peroxidase, and hydrogen peroxide (H 2 O 2 ) concentration in these animals before and after hypoxic-ischemic injury. Lipid peroxidation products were significantly increased 2 hours after the insult in both transgenic and nontransgenic brains in hippocampus, the most damaged brain region. Catalase activity did not increase in response to SOD1 overexpression or injury in either group. However, glutathione peroxidase activity, unchanged in response to overexpression, decreased significantly 24 hours after injury in both groups. At 24 hours after injury, greater H 2 O 2 accumulation was observed in transgenic brains. Because SOD1 dismutates superoxide to H 2 O 2 , overexpression of SOD1 in the presence of developmentally low activities of the catalytic enzymes glutathione peroxidase and catalase leads to an increased production of H 2 O 2 , and may explain the increased brain injury observed after Hypoxia-ischemia in neonatal SOD1 mice.
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brain injury after Perinatal Hypoxia ischemia is exacerbated in copper zinc superoxide dismutase transgenic mice
Pediatric Research, 1996Co-Authors: Jeremy S Ditelberg, Ann R Sheldon, Charles J Epstein, Donna M FerrieroAbstract:The role of superoxide radical formation in the pathogenesis of Perinatal hypoxic-ischemic injury was examined using transgenic (Tg) mice expressing three times normal amounts of copper/zinc-superoxide dismutase (CuZn/SOD). Fourteen litters of postnatal d 7 strain 218/3 mice were subjected to right common carotid artery ligation followed by 90 min of Hypoxia in an 8% oxygen/humidified chamber maintained at 37°C. Both Tg mice (n = 32) and their nontransgenic (nTg) littermates (n = 30) survived the injury equally. Evaluation of infarcted brain areas measured by video image analysis of three coronal brain sections through the anterior hippocampus from each animal revealed that the Tg animals suffered brain infarction more frequently than did nTg mice. Blinded histologic scoring of cerebral cortex and striatum 5 d after injury revealed that Tg mice were more likely to have higher histologic severity scores than their nTg littermates (p = 0.0463, Mann-Whitney U test). These findings suggest that brain injury in Perinatal Hypoxia-ischemia may be mediated in part by free radical formation from excessive hydrogen peroxide or nitric oxide production.
Frances E. Jensen - One of the best experts on this subject based on the ideXlab platform.
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NBQX or topiramate treatment after Perinatal Hypoxia-induced seizures prevents later increases in seizure-induced neuronal injury.
Epilepsia, 2004Co-Authors: Sookyong Koh, Felicia D. Tibayan, Joelle N Simpson, Frances E. JensenAbstract:Summary: Purpose: To evaluate the efficacy of NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f) quinoxaline-2,3-dione) and topiramate (TPM) given after Hypoxia-induced seizures in preventing the delayed effect of Hypoxia on subsequent susceptibility to seizures and neuronal injury. Methods: We used “two-hit” rodent seizure model to study the long-term effect of Perinatal Hypoxia on later kainate (KA) seizure-induced neuronal damage and investigated the therapeutic efficacy of a postseizure treatment protocol in reversing the conditioning effect of early-life seizures. Results: Hypoxia at P10 induces seizures without cell death but causes an increase in susceptibility to second seizures induced by KA as early as 96 h after Hypoxia, and this lowered seizure threshold persists to adulthood. Furthermore, Perinatal Hypoxia increases KA-induced neuronal injury at postnatal day (P)21 and 28/30. Repeated doses of NBQX (20 mg/kg) or TPM (30 mg/kg) given for 48 h after Hypoxia-induced seizures prevent the increase in susceptibility to KA seizure-induced hippocampal neuronal injury at P28/30. Conclusions: Our results suggest that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor blockade after Hypoxia prevents the priming effect of Perinatal Hypoxia-induced seizures and that this protection occurs independent of its anticonvulsant action.
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decreased glutamate receptor 2 expression and enhanced epileptogenesis in immature rat hippocampus after Perinatal Hypoxia induced seizures
The Journal of Neuroscience, 2001Co-Authors: Russell M Sanchez, Sookyong Koh, Carlos Rio, Carl Wang, Ed D Lamperti, Deepak Sharma, Gabriel Corfas, Frances E. JensenAbstract:Hypoxic encephalopathy is the most common cause of neonatal seizures and can lead to chronic epilepsy. In rats at postnatal days 10–12 (P10–12), global Hypoxia induces spontaneous seizures and chronically decreases seizure threshold, thus mimicking clinical aspects of neonatal Hypoxia. We have shown previously that the acute and chronic epileptogenic effects of Hypoxia are age-dependent and require AMPA receptor activation. In this study, we aimed to determine whether Hypoxia-induced seizures and epileptogenesis are associated with maturational and seizure-induced changes in AMPA receptor composition and function. Northern and Western blots indicated that glutamate receptor 2 (GluR2) mRNA and protein expression were significantly lower in neocortex and hippocampus at P10–12 compared with adult. After Hypoxia-induced seizures at P10, GluR2 mRNA was significantly decreased within 48 hr, and GluR2 protein was significantly decreased within 96 hr. AMPA-induced Co2+ uptake by neurons in hippocampal slices indicated higher expression of Ca2+-permeable AMPA receptors in immature pyramidal neurons compared with adult. In slices obtained 96 hr after Hypoxia-induced seizures, AMPA-induced Co2+ uptake was significantly increased compared with age-matched controls, and field recordings revealed increased tetanus-induced afterdischarges that could be kindled in the absence of NMDA receptor activation. In situ end labeling showed no acute or delayed cell death after Hypoxia-induced seizures. Our results indicate that susceptibility to Hypoxia-induced seizures occurs during a developmental stage in which the expression of Ca2+-permeable AMPA receptors is relatively high. Furthermore, Perinatal Hypoxia-induced seizures induce increased expression of Ca2+-permeable AMPA receptors and an increased capacity for AMPA receptor-mediated epileptogenesis without inducing cell death.
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topiramate blocks Perinatal Hypoxia induced seizures in rat pups
Annals of Neurology, 2001Co-Authors: Sookyong Koh, Frances E. JensenAbstract:Neonatal seizures caused by Hypoxia can be refractory to conventional anticonvulsants. Currently, there is no effective postnatal intervention for newborn infants with hypoxic encephalopathy to prevent brain injury and long-term neurologic sequelae. We previously developed a rat model of Perinatal Hypoxia-induced seizures with subsequent long-term increases in seizure susceptibility and showed that these epileptogenic effects are selectively blocked by the alpha-amino-3-hydoxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione. Using this model of Perinatal seizures, we evaluated the efficacy of topiramate, a structurally novel anticonvulsant drug recently shown to attenuate AMPA/kainate currents. Topiramate effectively suppressed acute seizures induced by Perinatal Hypoxia in a dose-related manner with a calculated ED50 of 2.1 mg/kg, i.p. Furthermore, in animals that had seizures suppressed by topiramate during acute Hypoxia, there were no long-term increases in susceptibility to kainate-induced seizures and seizure-induced neuronal injury. Our results suggest that topiramate may have clinical potential as a therapeutic agent for refractory seizures in human neonates.
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acute and chronic increases in excitability in rat hippocampal slices after Perinatal Hypoxia in vivo
Journal of Neurophysiology, 1998Co-Authors: Frances E. Jensen, C. Geary, Carl Wang, C E Stafstrom, Z Liu, M C StevensAbstract:We have previously shown that Hypoxia induces both acute and chronic epileptogenic effects that are age dependent. Global Hypoxia (3-4% O2) induces seizure activity in the developing brain [postnatal day (P)10-12] but not at younger or older ages. Adult rats with prior seizures induced by Hypoxia at P10 show increased seizure susceptibility to chemical convulsants compared with controls. In the present study, we tested the hypothesis that acute and chronic epileptogenic effects of Hypoxia are demonstrable in hippocampus both in vivo and in vitro. Depth electrode recordings confirmed the presence of ictal activity within hippocampus in P10 rats during global Hypoxia. Hippocampal slices prepared from P10 pups killed at 10 min after recovery from Hypoxia showed evidence of increased excitability. Extracellular field recordings revealed that the amplitude and duration of long-term potentiation (LTP) was increased significantly in area CA1 of hippocampal slices removed from hypoxic pups. In addition, extracellular recordings within areas CA1 and CA3 showed significantly longer afterdischarge durations in response to kindling stimuli in slices from hypoxic pups compared with controls. To evaluate whether there were also long-term changes in hippocampal excitability, hippocampal slices were prepared from adult rats that had underwent Hypoxia at P10 and compared with slices from adult litter-mate controls. A Mg2+-free medium was superfused to induce epileptiform activity within the slices. Extracellular recordings from stratum pyramidale of area CA1 showed that Mg2+-free media induced significantly more frequent ictal discharges in slices from previously hypoxic rats compared with controls. These results provide evidence that the naturally occurring stimulus of Hypoxia can result in both acute and chronic changes in the excitability of the CA1 neuronal network. These results parallel our previous in vivo studies demonstrating that global Hypoxia acutely increases excitability in the immature brain and that Hypoxia during the age window approximately P10 results in long-lasting increases in seizure susceptibility within hippocampus. Our results suggest that the age-dependent epileptogenic effects of Hypoxia are in part mediated by a direct and permanent effect on neuronal excitability within hippocampal neuronal networks.
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NBQX Blocks Acute and Late Epileptogenic Effects of Perinatal Hypoxia
Epilepsia, 1995Co-Authors: Frances E. Jensen, I. R. Firkusny, Howard W. Blume, S. Alvarado, C. GearyAbstract:Summary: Clinically, and in experimental models, Perinatal hypoxic encephalopathy is commonly associated with seizures. We previously described a rat model in which Hypoxia induces seizures and permanently increases in seizure susceptibility in immature rats [postnatal day (P) 10–121 but not in older rats. In the present study, we compared the effect of pretreatment with the excitatory amino acid antagonists MK-801 and NBQX versus lorazepam in our rat model of Perinatal Hypoxia. Animals exposed to Hypoxia at P10 without treatment have frequent seizures during Hypoxia and subsequently exhibit increased seizure susceptibility to flurothyl. Treatment with 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione(NBQX 20 mglkg) effectively suppressed Hypoxia-induced seizures in immature rats and also protected against permanent changes in flurothyl threshold in adult-hood, whereas treatment with MK-801 (1 mg/kg) or lorazepam (LZP 1 mg/kg) did not prevent these Hypoxia-related epileptogenic effects. These results suggest that activation of a-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) receptors may partly mediate the age-dependent epileptogenic effect of Hypoxia in the Perinatal period
Charles J Epstein - One of the best experts on this subject based on the ideXlab platform.
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copper zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after Perinatal Hypoxia ischemia
Annals of Neurology, 1998Co-Authors: Heather J Fullerton, Jeremy S Ditelberg, Charles J Epstein, Donna M Ferriero, Sylvia F Chen, Dean P Sarco, Pak H ChanAbstract:Unlike the mature animal, immature mice transgenic for copper/zinc superoxide dismutase (SODI) have greater brain injury after Hypoxia-ischemia than their wild-type nontransgenic littermates. To assess the role of oxidative stress in the pathogenesis of this injury, we measured histopathological damage, lipid peroxidation products, enzymatic activities of catalase and glutathione peroxidase, and hydrogen peroxide (H 2 O 2 ) concentration in these animals before and after hypoxic-ischemic injury. Lipid peroxidation products were significantly increased 2 hours after the insult in both transgenic and nontransgenic brains in hippocampus, the most damaged brain region. Catalase activity did not increase in response to SOD1 overexpression or injury in either group. However, glutathione peroxidase activity, unchanged in response to overexpression, decreased significantly 24 hours after injury in both groups. At 24 hours after injury, greater H 2 O 2 accumulation was observed in transgenic brains. Because SOD1 dismutates superoxide to H 2 O 2 , overexpression of SOD1 in the presence of developmentally low activities of the catalytic enzymes glutathione peroxidase and catalase leads to an increased production of H 2 O 2 , and may explain the increased brain injury observed after Hypoxia-ischemia in neonatal SOD1 mice.
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brain injury after Perinatal Hypoxia ischemia is exacerbated in copper zinc superoxide dismutase transgenic mice
Pediatric Research, 1996Co-Authors: Jeremy S Ditelberg, Ann R Sheldon, Charles J Epstein, Donna M FerrieroAbstract:The role of superoxide radical formation in the pathogenesis of Perinatal hypoxic-ischemic injury was examined using transgenic (Tg) mice expressing three times normal amounts of copper/zinc-superoxide dismutase (CuZn/SOD). Fourteen litters of postnatal d 7 strain 218/3 mice were subjected to right common carotid artery ligation followed by 90 min of Hypoxia in an 8% oxygen/humidified chamber maintained at 37°C. Both Tg mice (n = 32) and their nontransgenic (nTg) littermates (n = 30) survived the injury equally. Evaluation of infarcted brain areas measured by video image analysis of three coronal brain sections through the anterior hippocampus from each animal revealed that the Tg animals suffered brain infarction more frequently than did nTg mice. Blinded histologic scoring of cerebral cortex and striatum 5 d after injury revealed that Tg mice were more likely to have higher histologic severity scores than their nTg littermates (p = 0.0463, Mann-Whitney U test). These findings suggest that brain injury in Perinatal Hypoxia-ischemia may be mediated in part by free radical formation from excessive hydrogen peroxide or nitric oxide production.