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Shenandoah Robinson - One of the best experts on this subject based on the ideXlab platform.

  • repetitive neonatal erythropoietin and melatonin combinatorial treatment provides sustained repair of functional deficits in a rat model of cerebral palsy
    Frontiers in Neurology, 2018
    Co-Authors: Lauren L Jantzie, Akosua Y Oppong, Fatu S Conteh, Tracylyn R Yellowhair, Joshua Kim, Gabrielle Fink, Adam Wolin, Frances J Northington, Shenandoah Robinson
    Abstract:

    Cerebral palsy (CP) is the leading cause of motor impairment for children worldwide and results from perinatal brain Injury (PBI). To test novel therapeutics to mitigate deficits from PBI, we developed a rat model of extreme preterm birth (<28 weeks of gestation) that mimics dual intrauterine Injury from placental underperfusion and chorioamnionitis. We hypothesized that a sustained postnatal treatment regimen that combines the endogenous neuroreparative agents erythropoietin (EPO) and melatonin (MLT) would mitigate molecular, sensorimotor, and cognitive abnormalities in adults rats following Prenatal Injury. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague-Dawley rats. Uterine artery occlusion was performed for 60 min to induce placental insufficiency via transient systemic hypoxia-ischemia, followed by intra-amniotic injections of lipopolysaccharide, and laparotomy closure. On postnatal day 1 (P1), approximately equivalent to 30 weeks of gestation, injured rats were randomized to an extended EPO + MLT treatment regimen, or vehicle (sterile saline) from P1 to P10. Behavioral assays were performed along an extended developmental time course (n = 6-29). Open field testing shows injured rats exhibit hypermobility and disinhibition and that combined neonatal EPO + MLT treatment repairs disinhibition in injured rats, while EPO alone does not. Furthermore, EPO + MLT normalizes hindlimb deficits, including reduced paw area and paw pressure at peak stance, and elevated percent shared stance after Prenatal Injury. Injured rats had fewer social interactions than shams, and EPO + MLT normalized social drive. Touchscreen operant chamber testing of visual discrimination and reversal shows that EPO + MLT at least partially normalizes theses complex cognitive tasks. Together, these data indicate EPO + MLT can potentially repair multiple sensorimotor, cognitive, and behavioral realms following PBI, using highly translatable and sophisticated developmental testing platforms.

  • Erythropoietin attenuates loss of potassium chloride co-transporters following Prenatal brain Injury
    Molecular and Cellular Neuroscience, 2014
    Co-Authors: Lauren L Jantzie, Paulina M. Getsy, Daniel J. Firl, Christopher G. Wilson, Robert H. Miller, Shenandoah Robinson
    Abstract:

    Abstract Therapeutic agents that restore the inhibitory actions of γ-amino butyric acid (GABA) by modulating intracellular chloride concentrations will provide novel avenues to treat stroke, chronic pain, epilepsy, autism, and neurodegenerative and cognitive disorders. During development, upregulation of the potassium-chloride co-transporter KCC2, and the resultant switch from excitatory to inhibitory responses to GABA guide the formation of essential inhibitory circuits. Importantly, maturation of inhibitory mechanisms is also central to the development of excitatory circuits and proper balance between excitatory and inhibitory networks in the developing brain. Loss of KCC2 expression occurs in postmortem samples from human preterm infant brains with white matter lesions. Here we show that late gestation brain Injury in a rat model of extreme prematurity impairs the developmental upregulation of potassium chloride co-transporters during a critical postnatal period of circuit maturation in CA3 hippocampus by inducing a sustained loss of oligomeric KCC2 via a calpain-dependent mechanism. Further, administration of erythropoietin (EPO) in a clinically relevant postnatal dosing regimen following the Prenatal Injury protects the developing brain by reducing calpain activity, restoring oligomeric KCC2 expression and attenuating KCC2 fragmentation, thus providing the first report of a safe therapy to address deficits in KCC2 expression. Together, these data indicate it is possible to reverse abnormalities in KCC2 expression during the postnatal period, and potentially reverse deficits in inhibitory circuit formation central to cognitive impairment and epileptogenesis.

Fernando Cendes - One of the best experts on this subject based on the ideXlab platform.

  • Interrelationship of genetics and Prenatal Injury in the genesis of malformations of cortical development.
    JAMA Neurology, 2002
    Co-Authors: Maria Augusta Montenegro, C.a.m. Guerreiro, Iscia Lopes-cendes, Marilisa M. Guerreiro, Fernando Cendes
    Abstract:

    Patients and Design: A series of 76 consecutive patients with MCD and their families were systematically questioned about their family histories of epilepsy or other neurological impairment and the occurrence of Prenatal events. Whenever possible, magnetic resonance imaging was performed in other family members if MCD was suspected or in the presence of any neurological impairment. Patients were divided into 3 groups according to the type of MCD. Patients in group 1 had focal cortical dysplasia, group 2 had heterotopias (periventricular or subcortical) or agyria-pachygyria, and group 3 had polymicrogyria or schizencephaly. These findings were also compared with a disease-control group of 40 consecutive patients with epilepsy but without MCD. Setting: Neurology clinic of a university hospital. Results: Of the 76 patients with MCD, 21 (28%) had focal cortical dysplasia, 19 (25%) had heterotopias or agyria-pachygyria, and 36 (47%) had polymicrogyria or schizencephaly. There were 39 men and 37 women, aged 2 to 52 years (mean age, 13 years). In group 2, 6 patients (32%) had a family history of MCD, mental retardation, or miscarriages, suggesting a genetic predisposition. In group 3, family history of MCD was present in 5 patients (14%). Prenatal events occurred in 28 patients with MCD (37%) and 2 controls (5%) and were more frequent in patients with heterotopia or agyria-pachygyria and polymicrogyria (P .001). Conversely, epilepsy occurred in all patients in group 1, in 17 patients (89%) in group 2, and in 17 patients (47%) in group 3. In group 3, epilepsy was less frequent (P.001) and also more easily controlled (P = .005) than in other forms of MCD. Conclusions: Our findings support the idea of a spectrum among the different types of MCD. Focal cortical dysplasia (group 1) is associated with more frequent and severe epilepsy and less important genetic and Prenatal events, heterotopias and agyria-pachygyria (group 2) are frequently associated with genetic predisposition, and polymicrogyria and schizencephaly (group 3) are less frequently associated with epilepsy but have a stronger association with genetic and detectable Prenatal events.

Lauren L Jantzie - One of the best experts on this subject based on the ideXlab platform.

  • repetitive neonatal erythropoietin and melatonin combinatorial treatment provides sustained repair of functional deficits in a rat model of cerebral palsy
    Frontiers in Neurology, 2018
    Co-Authors: Lauren L Jantzie, Akosua Y Oppong, Fatu S Conteh, Tracylyn R Yellowhair, Joshua Kim, Gabrielle Fink, Adam Wolin, Frances J Northington, Shenandoah Robinson
    Abstract:

    Cerebral palsy (CP) is the leading cause of motor impairment for children worldwide and results from perinatal brain Injury (PBI). To test novel therapeutics to mitigate deficits from PBI, we developed a rat model of extreme preterm birth (<28 weeks of gestation) that mimics dual intrauterine Injury from placental underperfusion and chorioamnionitis. We hypothesized that a sustained postnatal treatment regimen that combines the endogenous neuroreparative agents erythropoietin (EPO) and melatonin (MLT) would mitigate molecular, sensorimotor, and cognitive abnormalities in adults rats following Prenatal Injury. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague-Dawley rats. Uterine artery occlusion was performed for 60 min to induce placental insufficiency via transient systemic hypoxia-ischemia, followed by intra-amniotic injections of lipopolysaccharide, and laparotomy closure. On postnatal day 1 (P1), approximately equivalent to 30 weeks of gestation, injured rats were randomized to an extended EPO + MLT treatment regimen, or vehicle (sterile saline) from P1 to P10. Behavioral assays were performed along an extended developmental time course (n = 6-29). Open field testing shows injured rats exhibit hypermobility and disinhibition and that combined neonatal EPO + MLT treatment repairs disinhibition in injured rats, while EPO alone does not. Furthermore, EPO + MLT normalizes hindlimb deficits, including reduced paw area and paw pressure at peak stance, and elevated percent shared stance after Prenatal Injury. Injured rats had fewer social interactions than shams, and EPO + MLT normalized social drive. Touchscreen operant chamber testing of visual discrimination and reversal shows that EPO + MLT at least partially normalizes theses complex cognitive tasks. Together, these data indicate EPO + MLT can potentially repair multiple sensorimotor, cognitive, and behavioral realms following PBI, using highly translatable and sophisticated developmental testing platforms.

  • Erythropoietin attenuates loss of potassium chloride co-transporters following Prenatal brain Injury
    Molecular and Cellular Neuroscience, 2014
    Co-Authors: Lauren L Jantzie, Paulina M. Getsy, Daniel J. Firl, Christopher G. Wilson, Robert H. Miller, Shenandoah Robinson
    Abstract:

    Abstract Therapeutic agents that restore the inhibitory actions of γ-amino butyric acid (GABA) by modulating intracellular chloride concentrations will provide novel avenues to treat stroke, chronic pain, epilepsy, autism, and neurodegenerative and cognitive disorders. During development, upregulation of the potassium-chloride co-transporter KCC2, and the resultant switch from excitatory to inhibitory responses to GABA guide the formation of essential inhibitory circuits. Importantly, maturation of inhibitory mechanisms is also central to the development of excitatory circuits and proper balance between excitatory and inhibitory networks in the developing brain. Loss of KCC2 expression occurs in postmortem samples from human preterm infant brains with white matter lesions. Here we show that late gestation brain Injury in a rat model of extreme prematurity impairs the developmental upregulation of potassium chloride co-transporters during a critical postnatal period of circuit maturation in CA3 hippocampus by inducing a sustained loss of oligomeric KCC2 via a calpain-dependent mechanism. Further, administration of erythropoietin (EPO) in a clinically relevant postnatal dosing regimen following the Prenatal Injury protects the developing brain by reducing calpain activity, restoring oligomeric KCC2 expression and attenuating KCC2 fragmentation, thus providing the first report of a safe therapy to address deficits in KCC2 expression. Together, these data indicate it is possible to reverse abnormalities in KCC2 expression during the postnatal period, and potentially reverse deficits in inhibitory circuit formation central to cognitive impairment and epileptogenesis.

Marilisa M. Guerreiro - One of the best experts on this subject based on the ideXlab platform.

  • Interrelationship of genetics and Prenatal Injury in the genesis of malformations of cortical development
    EUA, 2015
    Co-Authors: Marilisa M. Guerreiro, Guerreiro Cam, Cendes F
    Abstract:

    Context: Although the causes of some malformations of cortical development (MCD) have been established, others remain unclear. There are several lines of evidence supporting the theory of a complex mechanism that involves genetic and: environmental factors. Objective: To investigate the interrelationship of genetics and Prenatal Injury in the genesis of MCD. Patients and Design: A series of 76 consecutive patients with MCD and their families were systematically questioned about their family histories of epilepsy or other neurological impairment and the occurrence of Prenatal events. Whenever possible, magnetic resonance imaging was performed in other family members if MCD was suspected or in the presence of any neurological impairment. Patients were divided into 3 groups according to the type of MCD. Patients in group 1 had focal cortical dysplasia, group 2 had heterotopias (periventricular or subcortical) or agyria-pachygyria, and group 3 had polymicrogyria, or schizencephaly. These findings were also compared with a disease-control group of 40 consecutive patients with epilepsy but without MCD. Setting: Neurology clinic of a university hospital. Results: Of the 76 patients with MCD, 21 (28%) had focal cortical dysplasia, 19 (25%) had heterotopias or agyria-pachygyria, and 36 (47%) had polymicrogyria or schizencephaly, There were 39 men and 37 women, aged 2 to 52 years (mean age, 13 years). In group 2, 6 patients (32%) had a family history of MCD, mental retardation, or miscarriages, suggesting a genetic predisposition. In group 3, family history of MCD was present in 5 patients (14%). Prenatal events occurred in 28 patients with MCD (37%) and 2 controls (5%) and were more frequent in patients with heterotopia or agyria-pachygyria and polymicrogyria (P

  • Interrelationship of genetics and Prenatal Injury in the genesis of malformations of cortical development.
    JAMA Neurology, 2002
    Co-Authors: Maria Augusta Montenegro, C.a.m. Guerreiro, Iscia Lopes-cendes, Marilisa M. Guerreiro, Fernando Cendes
    Abstract:

    Patients and Design: A series of 76 consecutive patients with MCD and their families were systematically questioned about their family histories of epilepsy or other neurological impairment and the occurrence of Prenatal events. Whenever possible, magnetic resonance imaging was performed in other family members if MCD was suspected or in the presence of any neurological impairment. Patients were divided into 3 groups according to the type of MCD. Patients in group 1 had focal cortical dysplasia, group 2 had heterotopias (periventricular or subcortical) or agyria-pachygyria, and group 3 had polymicrogyria or schizencephaly. These findings were also compared with a disease-control group of 40 consecutive patients with epilepsy but without MCD. Setting: Neurology clinic of a university hospital. Results: Of the 76 patients with MCD, 21 (28%) had focal cortical dysplasia, 19 (25%) had heterotopias or agyria-pachygyria, and 36 (47%) had polymicrogyria or schizencephaly. There were 39 men and 37 women, aged 2 to 52 years (mean age, 13 years). In group 2, 6 patients (32%) had a family history of MCD, mental retardation, or miscarriages, suggesting a genetic predisposition. In group 3, family history of MCD was present in 5 patients (14%). Prenatal events occurred in 28 patients with MCD (37%) and 2 controls (5%) and were more frequent in patients with heterotopia or agyria-pachygyria and polymicrogyria (P .001). Conversely, epilepsy occurred in all patients in group 1, in 17 patients (89%) in group 2, and in 17 patients (47%) in group 3. In group 3, epilepsy was less frequent (P.001) and also more easily controlled (P = .005) than in other forms of MCD. Conclusions: Our findings support the idea of a spectrum among the different types of MCD. Focal cortical dysplasia (group 1) is associated with more frequent and severe epilepsy and less important genetic and Prenatal events, heterotopias and agyria-pachygyria (group 2) are frequently associated with genetic predisposition, and polymicrogyria and schizencephaly (group 3) are less frequently associated with epilepsy but have a stronger association with genetic and detectable Prenatal events.

Maria Augusta Montenegro - One of the best experts on this subject based on the ideXlab platform.

  • Interrelationship of genetics and Prenatal Injury in the genesis of malformations of cortical development.
    JAMA Neurology, 2002
    Co-Authors: Maria Augusta Montenegro, C.a.m. Guerreiro, Iscia Lopes-cendes, Marilisa M. Guerreiro, Fernando Cendes
    Abstract:

    Patients and Design: A series of 76 consecutive patients with MCD and their families were systematically questioned about their family histories of epilepsy or other neurological impairment and the occurrence of Prenatal events. Whenever possible, magnetic resonance imaging was performed in other family members if MCD was suspected or in the presence of any neurological impairment. Patients were divided into 3 groups according to the type of MCD. Patients in group 1 had focal cortical dysplasia, group 2 had heterotopias (periventricular or subcortical) or agyria-pachygyria, and group 3 had polymicrogyria or schizencephaly. These findings were also compared with a disease-control group of 40 consecutive patients with epilepsy but without MCD. Setting: Neurology clinic of a university hospital. Results: Of the 76 patients with MCD, 21 (28%) had focal cortical dysplasia, 19 (25%) had heterotopias or agyria-pachygyria, and 36 (47%) had polymicrogyria or schizencephaly. There were 39 men and 37 women, aged 2 to 52 years (mean age, 13 years). In group 2, 6 patients (32%) had a family history of MCD, mental retardation, or miscarriages, suggesting a genetic predisposition. In group 3, family history of MCD was present in 5 patients (14%). Prenatal events occurred in 28 patients with MCD (37%) and 2 controls (5%) and were more frequent in patients with heterotopia or agyria-pachygyria and polymicrogyria (P .001). Conversely, epilepsy occurred in all patients in group 1, in 17 patients (89%) in group 2, and in 17 patients (47%) in group 3. In group 3, epilepsy was less frequent (P.001) and also more easily controlled (P = .005) than in other forms of MCD. Conclusions: Our findings support the idea of a spectrum among the different types of MCD. Focal cortical dysplasia (group 1) is associated with more frequent and severe epilepsy and less important genetic and Prenatal events, heterotopias and agyria-pachygyria (group 2) are frequently associated with genetic predisposition, and polymicrogyria and schizencephaly (group 3) are less frequently associated with epilepsy but have a stronger association with genetic and detectable Prenatal events.