The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Joseph J. Volpe - One of the best experts on this subject based on the ideXlab platform.
-
Development/Plasticity/Repair Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role
2016Co-Authors: For Topiramate, Pamela L Follett, Delia M Talos, Leon Massillon, Wenbin Deng, Paul A Rosenberg, Joseph J. Volpe, Weimin Dai, Frances E JensenAbstract:Periventricular Leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA – kainate-type glutamate receptor blockade in a rodent model of periventricular Leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for periventricular Leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA – kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligoden-drocytes, similar to the AMPA – kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, pro-tective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA – kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular Leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter. Key words: white matter; glutamate receptor; periventricular Leukomalacia; topiramate; oligodendrocyte; excitotoxicit
-
neuron deficit in the white matter and subplate in periventricular Leukomalacia
Annals of Neurology, 2012Co-Authors: Hannah C Kinney, Rebecca D Folkerth, Robin L Haynes, Sarah E Andiman, Lynn A Sleeper, Joseph J. VolpeAbstract:Objective The cellular basis of cognitive abnormalities in preterm infants with periventricular Leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons which are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls.
-
the cerebral cortex overlying periventricular Leukomalacia analysis of pyramidal neurons
Brain Pathology, 2010Co-Authors: Sarah E Andiman, Joseph J. Volpe, Rebecca D Folkerth, Saraid S Billiards, Robin L Haynes, Felicia L Trachtenberg, Hannah C KinneyAbstract:The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular Leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.
-
myelin abnormalities without oligodendrocyte loss in periventricular Leukomalacia
Brain Pathology, 2008Co-Authors: Saraid S Billiards, Joseph J. Volpe, Rebecca D Folkerth, Robin L Haynes, Natalia S Borenstein, Felicia L Trachtenberg, David H Rowitch, Keith L Ligon, Hannah C KinneyAbstract:The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of periventricular Leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2. Myelination was assessed with myelin basic protein (MBP) immunostaining. We found no significant difference between PVL and control cases in Olig2 cell density in the periventricular or intragyral white matter. We did find, however, a significant increase in Olig2 cell density at the necrotic foci, compared with distant areas. Although no significant difference was found in the degree of MBP immunostaining, we observed qualitative abnormalities of MBP immunostaining in both the diffuse and necrotic components of PVL. Abnormal MBP immunostaining in PVL despite preserved Olig2 cell density may be secondary to arrested OL maturation, damage to OL processes, and/or impaired axonal-OL signaling. OL migration toward the "core" of injury may occur to replenish OL cell number. This study provides new insight into the cellular basis of the myelin deficits observed in survivors of PVL.
-
oxidative and nitrative injury in periventricular Leukomalacia a review
Brain Pathology, 2006Co-Authors: Robin L Haynes, Joseph J. Volpe, Olivier Baud, Rebecca D Folkerth, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL) is the major substrate of cerebral palsy in survivors of prematurity. Its pathogenesis is complex and likely involves ischemia/reperfusion in the critically ill premature infant, with impaired regulation of cerebral blood flow, as well as inflammatory mechanisms associated with maternal and/or fetal infection. During the peak period of vulnerability for PVL, developing oligodendrocytes (OLs) predominate in the white matter. We hypothesize that free radical injury to the developing OLs underlies, in part, the pathogenesis of PVL and the hypomyelination seen in long-term survivors. In human PVL, free radical injury is supported by evidence of oxidative and nitrative stress with markers to lipid peroxidation and nitrotyrosine, respectively. Evidence in normal human cerebral white matter suggests an underlying vulnerability of the premature infant to free radical injury resulting from a developmental mismatch of antioxidant enzymes (AOE) and subsequent imbalance in oxidant metabolism. In vitro studies using rodent OLs suggest that maturational susceptibility to reactive oxygen species is dependent, not only on levels of individual AOE, but also on specific interactions between these enzymes. Rodent in vitro data further suggest 2 mechanisms of nitric oxide damage: one involving the direct effect of nitric oxide on OL mitochondrial integrity and function, and the other involving an activation of microglia and subsequent release of reactive nitrogen species. The latter mechanism, while important in rodent studies, remains to be determined in the pathogenesis of human PVL. These observations together expand our knowledge of the role that free radical injury plays in the pathogenesis of PVL, and may contribute to the eventual development of therapeutic strategies to alleviate the burden of oxidative and nitrative injury in the premature infant at risk for PVL.
Hannah C Kinney - One of the best experts on this subject based on the ideXlab platform.
-
neuron deficit in the white matter and subplate in periventricular Leukomalacia
Annals of Neurology, 2012Co-Authors: Hannah C Kinney, Rebecca D Folkerth, Robin L Haynes, Sarah E Andiman, Lynn A Sleeper, Joseph J. VolpeAbstract:Objective The cellular basis of cognitive abnormalities in preterm infants with periventricular Leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons which are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls.
-
the cerebral cortex overlying periventricular Leukomalacia analysis of pyramidal neurons
Brain Pathology, 2010Co-Authors: Sarah E Andiman, Joseph J. Volpe, Rebecca D Folkerth, Saraid S Billiards, Robin L Haynes, Felicia L Trachtenberg, Hannah C KinneyAbstract:The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular Leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.
-
myelin abnormalities without oligodendrocyte loss in periventricular Leukomalacia
Brain Pathology, 2008Co-Authors: Saraid S Billiards, Joseph J. Volpe, Rebecca D Folkerth, Robin L Haynes, Natalia S Borenstein, Felicia L Trachtenberg, David H Rowitch, Keith L Ligon, Hannah C KinneyAbstract:The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of periventricular Leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2. Myelination was assessed with myelin basic protein (MBP) immunostaining. We found no significant difference between PVL and control cases in Olig2 cell density in the periventricular or intragyral white matter. We did find, however, a significant increase in Olig2 cell density at the necrotic foci, compared with distant areas. Although no significant difference was found in the degree of MBP immunostaining, we observed qualitative abnormalities of MBP immunostaining in both the diffuse and necrotic components of PVL. Abnormal MBP immunostaining in PVL despite preserved Olig2 cell density may be secondary to arrested OL maturation, damage to OL processes, and/or impaired axonal-OL signaling. OL migration toward the "core" of injury may occur to replenish OL cell number. This study provides new insight into the cellular basis of the myelin deficits observed in survivors of PVL.
-
oxidative and nitrative injury in periventricular Leukomalacia a review
Brain Pathology, 2006Co-Authors: Robin L Haynes, Joseph J. Volpe, Olivier Baud, Rebecca D Folkerth, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL) is the major substrate of cerebral palsy in survivors of prematurity. Its pathogenesis is complex and likely involves ischemia/reperfusion in the critically ill premature infant, with impaired regulation of cerebral blood flow, as well as inflammatory mechanisms associated with maternal and/or fetal infection. During the peak period of vulnerability for PVL, developing oligodendrocytes (OLs) predominate in the white matter. We hypothesize that free radical injury to the developing OLs underlies, in part, the pathogenesis of PVL and the hypomyelination seen in long-term survivors. In human PVL, free radical injury is supported by evidence of oxidative and nitrative stress with markers to lipid peroxidation and nitrotyrosine, respectively. Evidence in normal human cerebral white matter suggests an underlying vulnerability of the premature infant to free radical injury resulting from a developmental mismatch of antioxidant enzymes (AOE) and subsequent imbalance in oxidant metabolism. In vitro studies using rodent OLs suggest that maturational susceptibility to reactive oxygen species is dependent, not only on levels of individual AOE, but also on specific interactions between these enzymes. Rodent in vitro data further suggest 2 mechanisms of nitric oxide damage: one involving the direct effect of nitric oxide on OL mitochondrial integrity and function, and the other involving an activation of microglia and subsequent release of reactive nitrogen species. The latter mechanism, while important in rodent studies, remains to be determined in the pathogenesis of human PVL. These observations together expand our knowledge of the role that free radical injury plays in the pathogenesis of PVL, and may contribute to the eventual development of therapeutic strategies to alleviate the burden of oxidative and nitrative injury in the premature infant at risk for PVL.
-
interferon γ expression in periventricular Leukomalacia in the human brain
Brain Pathology, 2006Co-Authors: Joseph J. Volpe, Rebecca D Folkerth, Hannah C Kinney, Robin L Haynes, Felicia L Trachtenberg, Rachael J KeefeAbstract:Periventricular Leukomalacia (PVL), the major lesion underlying cerebral palsy in survivors of prematurity, is characterized by focal periventricular necrosis and diffuse gliosis of immature cerebral white matter. Causal roles have been ascribed to hypoxiaischemia and maternal-fetal infection, leading to cytokine responses, inflammation, and oligodendrocyte cell death. Because interferon-gamma (IFN-gamma) is directly toxic to immature oligodendrocytes, we tested the hypothesis that it is expressed in PVL (N = 13) compared to age-adjusted controls (N = 31) using immunocytochemistry. In PVL, IFN-gamma immunopositive macrophages were clustered in necrotic foci, and IFN-gamma immunopositive reactive astrocytes were present throughout the surrounding white matter (WM). The difference in the number of IFN-gamma immunopositive glial cells/high power field (IFN-gamma score, Grades 0-3) between PVL cases (age-adjusted mean 2.59+/-0.25) and controls (age-adjusted mean 1.39+/-0.16) was significant (p<0.001). In the gliotic WM, the IFN-gamma score correlated with markers for lipid peroxidation, but not nitrative stress. A subset of premyelinating (04+) oligodendrocytes expressed IFN-gamma receptors in PVL and control cases, indicating that these cells are vulnerable to IFN-gamma toxicity via receptor-mediated interactions. In PVL, IFN-gamma produced by macrophages and reactive astrocytes may play a role in cytokine-induced toxicity to premyelinating oligodendrocytes as part of a cytokine response stimulated by ischemia and/or infection.
Rebecca D Folkerth - One of the best experts on this subject based on the ideXlab platform.
-
neuron deficit in the white matter and subplate in periventricular Leukomalacia
Annals of Neurology, 2012Co-Authors: Hannah C Kinney, Rebecca D Folkerth, Robin L Haynes, Sarah E Andiman, Lynn A Sleeper, Joseph J. VolpeAbstract:Objective The cellular basis of cognitive abnormalities in preterm infants with periventricular Leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons which are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls.
-
the cerebral cortex overlying periventricular Leukomalacia analysis of pyramidal neurons
Brain Pathology, 2010Co-Authors: Sarah E Andiman, Joseph J. Volpe, Rebecca D Folkerth, Saraid S Billiards, Robin L Haynes, Felicia L Trachtenberg, Hannah C KinneyAbstract:The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular Leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.
-
myelin abnormalities without oligodendrocyte loss in periventricular Leukomalacia
Brain Pathology, 2008Co-Authors: Saraid S Billiards, Joseph J. Volpe, Rebecca D Folkerth, Robin L Haynes, Natalia S Borenstein, Felicia L Trachtenberg, David H Rowitch, Keith L Ligon, Hannah C KinneyAbstract:The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of periventricular Leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2. Myelination was assessed with myelin basic protein (MBP) immunostaining. We found no significant difference between PVL and control cases in Olig2 cell density in the periventricular or intragyral white matter. We did find, however, a significant increase in Olig2 cell density at the necrotic foci, compared with distant areas. Although no significant difference was found in the degree of MBP immunostaining, we observed qualitative abnormalities of MBP immunostaining in both the diffuse and necrotic components of PVL. Abnormal MBP immunostaining in PVL despite preserved Olig2 cell density may be secondary to arrested OL maturation, damage to OL processes, and/or impaired axonal-OL signaling. OL migration toward the "core" of injury may occur to replenish OL cell number. This study provides new insight into the cellular basis of the myelin deficits observed in survivors of PVL.
-
oxidative and nitrative injury in periventricular Leukomalacia a review
Brain Pathology, 2006Co-Authors: Robin L Haynes, Joseph J. Volpe, Olivier Baud, Rebecca D Folkerth, Hannah C KinneyAbstract:Periventricular Leukomalacia (PVL) is the major substrate of cerebral palsy in survivors of prematurity. Its pathogenesis is complex and likely involves ischemia/reperfusion in the critically ill premature infant, with impaired regulation of cerebral blood flow, as well as inflammatory mechanisms associated with maternal and/or fetal infection. During the peak period of vulnerability for PVL, developing oligodendrocytes (OLs) predominate in the white matter. We hypothesize that free radical injury to the developing OLs underlies, in part, the pathogenesis of PVL and the hypomyelination seen in long-term survivors. In human PVL, free radical injury is supported by evidence of oxidative and nitrative stress with markers to lipid peroxidation and nitrotyrosine, respectively. Evidence in normal human cerebral white matter suggests an underlying vulnerability of the premature infant to free radical injury resulting from a developmental mismatch of antioxidant enzymes (AOE) and subsequent imbalance in oxidant metabolism. In vitro studies using rodent OLs suggest that maturational susceptibility to reactive oxygen species is dependent, not only on levels of individual AOE, but also on specific interactions between these enzymes. Rodent in vitro data further suggest 2 mechanisms of nitric oxide damage: one involving the direct effect of nitric oxide on OL mitochondrial integrity and function, and the other involving an activation of microglia and subsequent release of reactive nitrogen species. The latter mechanism, while important in rodent studies, remains to be determined in the pathogenesis of human PVL. These observations together expand our knowledge of the role that free radical injury plays in the pathogenesis of PVL, and may contribute to the eventual development of therapeutic strategies to alleviate the burden of oxidative and nitrative injury in the premature infant at risk for PVL.
-
interferon γ expression in periventricular Leukomalacia in the human brain
Brain Pathology, 2006Co-Authors: Joseph J. Volpe, Rebecca D Folkerth, Hannah C Kinney, Robin L Haynes, Felicia L Trachtenberg, Rachael J KeefeAbstract:Periventricular Leukomalacia (PVL), the major lesion underlying cerebral palsy in survivors of prematurity, is characterized by focal periventricular necrosis and diffuse gliosis of immature cerebral white matter. Causal roles have been ascribed to hypoxiaischemia and maternal-fetal infection, leading to cytokine responses, inflammation, and oligodendrocyte cell death. Because interferon-gamma (IFN-gamma) is directly toxic to immature oligodendrocytes, we tested the hypothesis that it is expressed in PVL (N = 13) compared to age-adjusted controls (N = 31) using immunocytochemistry. In PVL, IFN-gamma immunopositive macrophages were clustered in necrotic foci, and IFN-gamma immunopositive reactive astrocytes were present throughout the surrounding white matter (WM). The difference in the number of IFN-gamma immunopositive glial cells/high power field (IFN-gamma score, Grades 0-3) between PVL cases (age-adjusted mean 2.59+/-0.25) and controls (age-adjusted mean 1.39+/-0.16) was significant (p<0.001). In the gliotic WM, the IFN-gamma score correlated with markers for lipid peroxidation, but not nitrative stress. A subset of premyelinating (04+) oligodendrocytes expressed IFN-gamma receptors in PVL and control cases, indicating that these cells are vulnerable to IFN-gamma toxicity via receptor-mediated interactions. In PVL, IFN-gamma produced by macrophages and reactive astrocytes may play a role in cytokine-induced toxicity to premyelinating oligodendrocytes as part of a cytokine response stimulated by ischemia and/or infection.
Frances E Jensen - One of the best experts on this subject based on the ideXlab platform.
-
Development/Plasticity/Repair Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role
2016Co-Authors: For Topiramate, Pamela L Follett, Delia M Talos, Leon Massillon, Wenbin Deng, Paul A Rosenberg, Joseph J. Volpe, Weimin Dai, Frances E JensenAbstract:Periventricular Leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA – kainate-type glutamate receptor blockade in a rodent model of periventricular Leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for periventricular Leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA – kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligoden-drocytes, similar to the AMPA – kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, pro-tective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA – kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular Leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter. Key words: white matter; glutamate receptor; periventricular Leukomalacia; topiramate; oligodendrocyte; excitotoxicit
-
Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular Leukomalacia.
Pediatric research, 2015Co-Authors: Lauren L. Jantzie, Hyun-kyung Park, Michele Jackson, Jessie R. Maxwell, Frances E JensenAbstract:Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular Leukomalacia
-
glutamate receptor mediated oligodendrocyte toxicity in periventricular Leukomalacia a protective role for topiramate
The Journal of Neuroscience, 2004Co-Authors: Pamela L Follett, Delia M Talos, Leon Massillon, Wenbin Deng, Paul A Rosenberg, Joseph J. Volpe, Frances E JensenAbstract:Periventricular Leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA–kainate-type glutamate receptor blockade in a rodent model of periventricular Leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for periventricular Leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo , is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA–kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA–kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro . Taken together, these results suggest that AMPA–kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular Leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.
Wenbin Deng - One of the best experts on this subject based on the ideXlab platform.
-
Development/Plasticity/Repair Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role
2016Co-Authors: For Topiramate, Pamela L Follett, Delia M Talos, Leon Massillon, Wenbin Deng, Paul A Rosenberg, Joseph J. Volpe, Weimin Dai, Frances E JensenAbstract:Periventricular Leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA – kainate-type glutamate receptor blockade in a rodent model of periventricular Leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for periventricular Leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA – kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligoden-drocytes, similar to the AMPA – kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, pro-tective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA – kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular Leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter. Key words: white matter; glutamate receptor; periventricular Leukomalacia; topiramate; oligodendrocyte; excitotoxicit
-
the vulnerability of thalamocortical circuitry to hypoxic ischemic injury in a mouse model of periventricular Leukomalacia
BMC Neuroscience, 2016Co-Authors: Xiao Bo Liu, Yan Shen, David E Pleasure, Wenbin DengAbstract:Background Periventricular Leukomalacia (PVL) is the leading cause of neurological disabilities including motor and cognitive deficits in premature infants. Periventricular Leukomalacia is characterized by damage to the white matter in the immature brain, but the mechanisms by which damage to immature white matter results in widespread deficits of cognitive and motor function are unclear. The thalamocortical system is crucial for human consciousness and cognitive functions, and impaired development of the cortico-thalamic projections in the neonatal period is implicated to contribute importantly to abnormalities of cognitive function in children with PVL.
-
mouse models of periventricular Leukomalacia
Journal of Visualized Experiments, 2010Co-Authors: Yan Shen, Jennifer M Plane, Wenbin DengAbstract: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.
-
progress in periventricular Leukomalacia
JAMA Neurology, 2008Co-Authors: Wenbin Deng, Jeanette R Pleasure, David E PleasureAbstract:Periventricular Leukomalacia (PVL) is the predominant form of brain injury and the leading known cause of cerebral palsy and cognitive deficits in premature infants. The number of low-birth-weight infants who survive to demonstrate these neurologic deficts is increasing.Magneticresonanceimaging–basedneuroimagingtechniquesprovidegreater diagnostic sensitivity for PVL than does head ultrasonography and often document the involvement of telencephalic gray matter and long tracts in addition to periventricular white matter. The neuropathologic hallmarks of PVL are microglial activation and focal and diffuse periventricular depletion of premyelinating oligodendroglia. Premyelinating oligodendroglia are highly vulnerable to death caused by glutamate, free radicals, and proinflammatory cytokines. Studies in animal models of PVL suggest that pharmacologic interventions that target these toxic molecules will be useful in diminishing the severity of PVL.
-
glutamate receptor mediated oligodendrocyte toxicity in periventricular Leukomalacia a protective role for topiramate
The Journal of Neuroscience, 2004Co-Authors: Pamela L Follett, Delia M Talos, Leon Massillon, Wenbin Deng, Paul A Rosenberg, Joseph J. Volpe, Frances E JensenAbstract:Periventricular Leukomalacia is a form of hypoxic–ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic–ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA–kainate-type glutamate receptor blockade in a rodent model of periventricular Leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic–ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23–32 weeks gestation, the period of highest risk for periventricular Leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo , is protective against selective hypoxic–ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA–kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA–kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro . Taken together, these results suggest that AMPA–kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular Leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.