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Floris Groenendaal - One of the best experts on this subject based on the ideXlab platform.

  • Cerebral Cortical Tissue damage after hemorrhagic hypotension in near term born lambs
    Pediatric Research, 2006
    Co-Authors: Evelyn Van Den Tweel, Hans Egberts, Jeroen C.w. Hopman, Wim Ruitenbeek, Floris Groenendaal
    Abstract:

    Hypotension reduces Cerebral O(2) supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the Cerebral cortex, as measured with electroCortical brain activity (ECBA), is related to Cerebral Cortical Tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of Cerebral Cortical Tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O(2) supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO(2) and NO(3) (NOx) in plasma, and cGMP in Cortical brain Tissue were determined in both conditions. CSF and brain Tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the Cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, Cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of Cerebral Cortical damage.

  • Cerebral Cortical Tissue damage after hemorrhagic hypotension in near term born lambs
    Pediatric Research, 2006
    Co-Authors: Evelyn Van Den Tweel, Hans Egberts, Jeroen C.w. Hopman, Wim Ruitenbeek, Floris Groenendaal
    Abstract:

    Hypotension reduces Cerebral O(2) supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the Cerebral cortex, as measured with electroCortical brain activity (ECBA), is related to Cerebral Cortical Tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of Cerebral Cortical Tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O(2) supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO(2) and NO(3) (NOx) in plasma, and cGMP in Cortical brain Tissue were determined in both conditions. CSF and brain Tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the Cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, Cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of Cerebral Cortical damage.

  • function of cell membranes in Cerebral Cortical Tissue of newborn piglets after hypoxia and inhibition of nitric oxide synthase
    Pediatric Research, 1997
    Co-Authors: Floris Groenendaal, Om P Mishra, Jane E Mcgowan, David J Hoffman, Maria Delivoriapapadopoulos
    Abstract:

    Hypoxia-induced brain cell membrane lipid peroxidation can be caused by free radicals that are produced during hypoxia. Recently, the production of nitric oxide (NO), a free radical, has been shown to be increased during Cerebral hypoxia-ischemia. The present study tested the hypothesis that inhibition of NO synthase (NOS) reduced hypoxia-induced modifications of Na+,K+-ATPase activity, lipid peroxidation, and [3H]MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor in Cerebral Cortical Tissue of newborn piglets. Studies were performed in 26 newborn piglets. Cerebral NOS was inhibited by the i.v. administration of 25 or 50 mg/kg N(omega)-nitro-L-arginine (NNLA) over 30 min. Control animals received normal saline. Six groups of piglets were thus created (normoxia, no NNLA; normoxia + NNLA 25 mg/kg; normoxia + NNLA 50 mg/kg; hypoxia, no NNLA; hypoxia + NNLA 25 mg/kg; hypoxia + NNLA 50 mg/kg). One hour after the start of NNLA or saline infusion, hypoxia was induced by lowering the FiO2 to 0.07 in the three hypoxia groups, whereas in the three other groups normoxia was maintained. After 60 min of hypoxia, the brain was taken out and frozen. NOS activity, Na+,K+-ATPase activity, conjugated dienes, and [3H]MK-801 binding to the NMDA receptor of Cerebral Cortical Tissue were determined. NOS activity was reduced to 34% of its baseline value with NNLA 25 mg/kg, and to 19-27% of its baseline value with NNLA 50 mg/kg, respectively. Administration of NNLA did neither significantly alter the hypoxia-induced production of conjugated dienes, indicating lipid peroxidation nor the decrease of Na+,K+-ATPase activity after hypoxia. [3H]MK-801 binding studies of the NMDA receptor, however, showed that NNLA preserved Bmax and Kd after hypoxia. We conclude that inhibition of NOS does not change the hypoxia-induced decrease of Na+,K+-ATPase activity and production of conjugated dienes in brain cell membranes. Inhibition of NOS preserved the binding of [3H]MK-801 to the NMDA receptor after hypoxia.

  • effect of deferoxamine dfo administration on nonprotein bound iron npbi and total iron content of Cerebral Cortical Tissue of newborn lambs following hypoxia ischemia 187
    Pediatric Research, 1997
    Co-Authors: Floris Groenendaal, Majidah Shadid, Giuseppe Buonocore, Marco Ferrali, Lennard Hiltermann, Frank Van Bel
    Abstract:

    EFFECT OF DEFEROXAMINE (DFO) ADMINISTRATION ON NONPROTEIN-BOUND IRON (NPBI) AND TOTAL IRON CONTENT OF Cerebral Cortical Tissue OF NEWBORN LAMBS FOLLOWING HYPOXIA-ISCHEMIA. • 187

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

  • hypoxia induced bax and bcl 2 protein expression caspase 9 activation dna fragmentation and lipid peroxidation in mitochondria of the Cerebral cortex of newborn piglets the role of nitric oxide
    Neuroscience, 2006
    Co-Authors: Om P Mishra, Qazi M Ashraf, T Randis, Maria Delivoriapapadopoulos
    Abstract:

    Abstract The present study tests the hypothesis that Cerebral hypoxia results in increased ratio of Bax/Bcl-2, activation of caspase-9, lipid peroxidation, and DNA fragmentation in mitochondria of the Cerebral cortex of newborn piglets and that the inhibition of nitric oxide synthase by N -nitro- l -arginine during hypoxia will prevent the events leading to mitochondrial DNA fragmentation. To test this hypothesis, six piglets, 3–5 days old, were divided into three groups: normoxic ( n =5), hypoxic ( n =5), and hypoxic–nitric oxide synthase ( n =4). Hypoxic animals were exposed to a FiO 2 of 0.6 for 60 min. Nitric oxide synthase (40 mg/kg) was infused over 60 min prior to hypoxia. Tissue hypoxia was confirmed by measuring levels of ATP and phosphocreatine. Cerebral Cortical Tissue mitochondria were isolated and purified using a discontinuous ficoll gradient. Mitochondrial Bax and Bcl-2 proteins were determined by Western blot. Caspase-9 activity in mitochondria was determined spectro-fluorometrically using fluorogenic substrate for caspase-9. Fluorescent compounds, an index of mitochondrial membrane lipid peroxidation, were determined spectrofluorometrically. Mitochondrial DNA was isolated and separated by electrophoresis on 1% agarose gel and stained with ethidium bromide. ATP levels (μmol/g brain) were 4.52±0.34 in normoxic, 1.18±0.29 in hypoxic ( P P P P P =NS vs. hypoxic). Bax density in mitochondrial membranes was 160±28 in normoxic and 324±65 in hypoxic ( P P =NS vs. normoxic). Mitochondrial caspase-9 activity (nmol/mg protein/h) was 1.32±0.23 in normoxic and 2.25±0.24 in hypoxic ( P P =0.003 vs. normoxic). Densities (OD×mm 2 ) of low molecular weight DNA fragments were 143±38 in normoxic, 365±152 in hypoxic, ( P P P =NS vs. normoxic). The data demonstrate that hypoxia results in increased mitochondrial proapoptotic protein Bax, increased mitochondrial caspase-9 activity, increased mitochondrial lipid peroxidation, and increased fragmentation of DNA in mitochondria of the Cerebral cortex of newborn piglets. The administration of a nitric oxide synthase inhibitor, nitric oxide synthase, prior to hypoxia prevented fragmentation of mitochondrial DNA, indicating that the hypoxia-induced mitochondrial DNA fragmentation is NO-mediated. We propose that NO free radicals generated during hypoxia lead to NO-mediated altered expression of Bax leading to increased ratio of pro-apoptotic/anti-apoptotic protein resulting in modification of mitochondrial membrane, and subsequently Ca 2+ -influx and fragmentation of mitochondrial DNA.

  • effect of hypoxia on calcium influx and calcium calmodulin dependent kinase activity in Cortical neuronal nuclei of the guinea pig fetus during development
    American Journal of Obstetrics and Gynecology, 2002
    Co-Authors: Dev Maulik, Om P Mishra, Qazi M Ashraf, Maria Delivoriapapadopoulos
    Abstract:

    OBJECTIVE: Our purpose was to investigate the effect of hypoxia on calcium (Ca(++)) influx and Ca(++)-calmodulin (CaM)-dependent protein kinase IV (CaM kinase IV) activity in the neuronal nuclei of the guinea pig fetal Cerebral cortex during development. STUDY DESIGN: Preterm and term pregnant guinea pigs (n = 61) were exposed to either 21% or 7% oxygen for 60 minutes. Hypoxia in the fetal Cerebral Cortical Tissue was documented by determining the Tissue concentrations of adenosine triphosphate (ATP) and phosphocreatine. Fetal Cerebral Cortical neuronal nuclei were isolated and purified, and ATP-dependent Ca(++) influx and CaM kinase activity were determined. RESULTS: Hypoxia resulted in increased neuronal intranuclear (45)Ca(++) influx for 2 minutes from 6.65 +/- 1.29 pmol/mg protein to 9.07 +/- 1.98 pmol/mg protein (P <.05) in preterm and from 6.65 +/- 1.63 pmol/mg protein to 11.26 +/- 1.79 pmol/mg protein (P <.05) in term fetuses. The hypoxia-induced (45)Ca(++) influx was significantly higher (P <.05) in the term than in the preterm fetuses. Hypoxia resulted in increased CaM kinase IV activity from 383.7 +/- 53.3 pmol/mg/min protein to 451.6 +/- 59.5 pmol/mg/min protein (P <.05) in the preterm and from 364.6 +/- 109.7 pmol/mg/min protein to 487.0 +/- 43.3 pmol/mg/min protein (P < 0.05) in term fetuses. No significant difference was observed in CaM kinase IV activity between the preterm and the term groups. CONCLUSION: Cerebral hypoxia increases calcium influx and CaM kinase IV activity in the Cortical neuronal nuclei of the guinea pig fetal brain during development.

  • function of cell membranes in Cerebral Cortical Tissue of newborn piglets after hypoxia and inhibition of nitric oxide synthase
    Pediatric Research, 1997
    Co-Authors: Floris Groenendaal, Om P Mishra, Jane E Mcgowan, David J Hoffman, Maria Delivoriapapadopoulos
    Abstract:

    Hypoxia-induced brain cell membrane lipid peroxidation can be caused by free radicals that are produced during hypoxia. Recently, the production of nitric oxide (NO), a free radical, has been shown to be increased during Cerebral hypoxia-ischemia. The present study tested the hypothesis that inhibition of NO synthase (NOS) reduced hypoxia-induced modifications of Na+,K+-ATPase activity, lipid peroxidation, and [3H]MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor in Cerebral Cortical Tissue of newborn piglets. Studies were performed in 26 newborn piglets. Cerebral NOS was inhibited by the i.v. administration of 25 or 50 mg/kg N(omega)-nitro-L-arginine (NNLA) over 30 min. Control animals received normal saline. Six groups of piglets were thus created (normoxia, no NNLA; normoxia + NNLA 25 mg/kg; normoxia + NNLA 50 mg/kg; hypoxia, no NNLA; hypoxia + NNLA 25 mg/kg; hypoxia + NNLA 50 mg/kg). One hour after the start of NNLA or saline infusion, hypoxia was induced by lowering the FiO2 to 0.07 in the three hypoxia groups, whereas in the three other groups normoxia was maintained. After 60 min of hypoxia, the brain was taken out and frozen. NOS activity, Na+,K+-ATPase activity, conjugated dienes, and [3H]MK-801 binding to the NMDA receptor of Cerebral Cortical Tissue were determined. NOS activity was reduced to 34% of its baseline value with NNLA 25 mg/kg, and to 19-27% of its baseline value with NNLA 50 mg/kg, respectively. Administration of NNLA did neither significantly alter the hypoxia-induced production of conjugated dienes, indicating lipid peroxidation nor the decrease of Na+,K+-ATPase activity after hypoxia. [3H]MK-801 binding studies of the NMDA receptor, however, showed that NNLA preserved Bmax and Kd after hypoxia. We conclude that inhibition of NOS does not change the hypoxia-induced decrease of Na+,K+-ATPase activity and production of conjugated dienes in brain cell membranes. Inhibition of NOS preserved the binding of [3H]MK-801 to the NMDA receptor after hypoxia.

  • mechanism of hypoxia induced modification of nmda receptor activity in guinea pig fetus brain 1744
    Pediatric Research, 1997
    Co-Authors: Om P Mishra, Endla K Anday, Santina Zanelli, Maria Delivoriapapadopoulos
    Abstract:

    Our previous studies have shown that hypoxia modifies the NMDA(N-methyl-D-aspartate) receptor in the brain, resulting in decreased Bmax(number of functional receptor ion-channels) and decreased Kd (apparent affinity) and that alteration of the NMDA receptor is related to brain Tissue levels of high energy phosphates (ATP and phosphocreatine). The present study tests the hypothesis that the altered structure of the NMDA receptor during hypoxia is due to dephosphorylation. Guinea pig fetuses were obtained from anesthetized, normoxic (21% oxygen, n=6) and hypoxic (7% oxygen for 60 min, n=6) mothers. Brain Tissue hypoxia in the fetus was documented biochemically by decreased levels of ATP and phosphocreatine. P2 membrane fractions were prepared from fetal Cerebral Cortical Tissue. Both the normoxic and hypoxic membranes were incubated with 10 units of alkaline phosphatase for 30 min. at pH 9.0 NMDA receptor ion channel activity was measured using 3MK-801 binding as an index of receptor function. The results show that in normoxic membranes, enzyme treatment decreased the Bmax from 07.0±0.03 to 0.48±0.02 pmols/mg protein, (p<0.005). The Kd value decreased from 7.5±0.4 to 3.9±0.3 nM (p<0.005). In hypoxic membranes, enzyme treatment had no effect either on the Bmax (0.50±0.021 vs 0.50±0.020 pmols/mg protein, untreated vs treated) or the Kd(4.5±0.3 vs 4.3±0.2 nM, untreated vs treated). Bmax and Kd in untreated hypoxic brain were similar to the results obtained using enzyme treatment leading to dephosphorylation in normoxic brain. The data suggest that, during normoxia, NMDA receptor ion channel function may be regulated by phosphorylation/dephosphorylation and that hypoxia results in dephosphorylation of the NMDA receptor ion channel. We speculate that the increased affinity of the NMDA receptor ion-channel in the dephosphorylated state leads to the initiation of NMDA receptor-mediated events and may be a mechanism of neuronal injury during hypoxia. (Supported by NIH-20337)

Evelyn Van Den Tweel - One of the best experts on this subject based on the ideXlab platform.

  • Cerebral Cortical Tissue damage after hemorrhagic hypotension in near term born lambs
    Pediatric Research, 2006
    Co-Authors: Evelyn Van Den Tweel, Hans Egberts, Jeroen C.w. Hopman, Wim Ruitenbeek, Floris Groenendaal
    Abstract:

    Hypotension reduces Cerebral O(2) supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the Cerebral cortex, as measured with electroCortical brain activity (ECBA), is related to Cerebral Cortical Tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of Cerebral Cortical Tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O(2) supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO(2) and NO(3) (NOx) in plasma, and cGMP in Cortical brain Tissue were determined in both conditions. CSF and brain Tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the Cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, Cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of Cerebral Cortical damage.

  • Cerebral Cortical Tissue damage after hemorrhagic hypotension in near term born lambs
    Pediatric Research, 2006
    Co-Authors: Evelyn Van Den Tweel, Hans Egberts, Jeroen C.w. Hopman, Wim Ruitenbeek, Floris Groenendaal
    Abstract:

    Hypotension reduces Cerebral O(2) supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the Cerebral cortex, as measured with electroCortical brain activity (ECBA), is related to Cerebral Cortical Tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of Cerebral Cortical Tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O(2) supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO(2) and NO(3) (NOx) in plasma, and cGMP in Cortical brain Tissue were determined in both conditions. CSF and brain Tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the Cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, Cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of Cerebral Cortical damage.

Om P Mishra - One of the best experts on this subject based on the ideXlab platform.

  • hypoxia induced bax and bcl 2 protein expression caspase 9 activation dna fragmentation and lipid peroxidation in mitochondria of the Cerebral cortex of newborn piglets the role of nitric oxide
    Neuroscience, 2006
    Co-Authors: Om P Mishra, Qazi M Ashraf, T Randis, Maria Delivoriapapadopoulos
    Abstract:

    Abstract The present study tests the hypothesis that Cerebral hypoxia results in increased ratio of Bax/Bcl-2, activation of caspase-9, lipid peroxidation, and DNA fragmentation in mitochondria of the Cerebral cortex of newborn piglets and that the inhibition of nitric oxide synthase by N -nitro- l -arginine during hypoxia will prevent the events leading to mitochondrial DNA fragmentation. To test this hypothesis, six piglets, 3–5 days old, were divided into three groups: normoxic ( n =5), hypoxic ( n =5), and hypoxic–nitric oxide synthase ( n =4). Hypoxic animals were exposed to a FiO 2 of 0.6 for 60 min. Nitric oxide synthase (40 mg/kg) was infused over 60 min prior to hypoxia. Tissue hypoxia was confirmed by measuring levels of ATP and phosphocreatine. Cerebral Cortical Tissue mitochondria were isolated and purified using a discontinuous ficoll gradient. Mitochondrial Bax and Bcl-2 proteins were determined by Western blot. Caspase-9 activity in mitochondria was determined spectro-fluorometrically using fluorogenic substrate for caspase-9. Fluorescent compounds, an index of mitochondrial membrane lipid peroxidation, were determined spectrofluorometrically. Mitochondrial DNA was isolated and separated by electrophoresis on 1% agarose gel and stained with ethidium bromide. ATP levels (μmol/g brain) were 4.52±0.34 in normoxic, 1.18±0.29 in hypoxic ( P P P P P =NS vs. hypoxic). Bax density in mitochondrial membranes was 160±28 in normoxic and 324±65 in hypoxic ( P P =NS vs. normoxic). Mitochondrial caspase-9 activity (nmol/mg protein/h) was 1.32±0.23 in normoxic and 2.25±0.24 in hypoxic ( P P =0.003 vs. normoxic). Densities (OD×mm 2 ) of low molecular weight DNA fragments were 143±38 in normoxic, 365±152 in hypoxic, ( P P P =NS vs. normoxic). The data demonstrate that hypoxia results in increased mitochondrial proapoptotic protein Bax, increased mitochondrial caspase-9 activity, increased mitochondrial lipid peroxidation, and increased fragmentation of DNA in mitochondria of the Cerebral cortex of newborn piglets. The administration of a nitric oxide synthase inhibitor, nitric oxide synthase, prior to hypoxia prevented fragmentation of mitochondrial DNA, indicating that the hypoxia-induced mitochondrial DNA fragmentation is NO-mediated. We propose that NO free radicals generated during hypoxia lead to NO-mediated altered expression of Bax leading to increased ratio of pro-apoptotic/anti-apoptotic protein resulting in modification of mitochondrial membrane, and subsequently Ca 2+ -influx and fragmentation of mitochondrial DNA.

  • effect of hypoxia on calcium influx and calcium calmodulin dependent kinase activity in Cortical neuronal nuclei of the guinea pig fetus during development
    American Journal of Obstetrics and Gynecology, 2002
    Co-Authors: Dev Maulik, Om P Mishra, Qazi M Ashraf, Maria Delivoriapapadopoulos
    Abstract:

    OBJECTIVE: Our purpose was to investigate the effect of hypoxia on calcium (Ca(++)) influx and Ca(++)-calmodulin (CaM)-dependent protein kinase IV (CaM kinase IV) activity in the neuronal nuclei of the guinea pig fetal Cerebral cortex during development. STUDY DESIGN: Preterm and term pregnant guinea pigs (n = 61) were exposed to either 21% or 7% oxygen for 60 minutes. Hypoxia in the fetal Cerebral Cortical Tissue was documented by determining the Tissue concentrations of adenosine triphosphate (ATP) and phosphocreatine. Fetal Cerebral Cortical neuronal nuclei were isolated and purified, and ATP-dependent Ca(++) influx and CaM kinase activity were determined. RESULTS: Hypoxia resulted in increased neuronal intranuclear (45)Ca(++) influx for 2 minutes from 6.65 +/- 1.29 pmol/mg protein to 9.07 +/- 1.98 pmol/mg protein (P <.05) in preterm and from 6.65 +/- 1.63 pmol/mg protein to 11.26 +/- 1.79 pmol/mg protein (P <.05) in term fetuses. The hypoxia-induced (45)Ca(++) influx was significantly higher (P <.05) in the term than in the preterm fetuses. Hypoxia resulted in increased CaM kinase IV activity from 383.7 +/- 53.3 pmol/mg/min protein to 451.6 +/- 59.5 pmol/mg/min protein (P <.05) in the preterm and from 364.6 +/- 109.7 pmol/mg/min protein to 487.0 +/- 43.3 pmol/mg/min protein (P < 0.05) in term fetuses. No significant difference was observed in CaM kinase IV activity between the preterm and the term groups. CONCLUSION: Cerebral hypoxia increases calcium influx and CaM kinase IV activity in the Cortical neuronal nuclei of the guinea pig fetal brain during development.

  • function of cell membranes in Cerebral Cortical Tissue of newborn piglets after hypoxia and inhibition of nitric oxide synthase
    Pediatric Research, 1997
    Co-Authors: Floris Groenendaal, Om P Mishra, Jane E Mcgowan, David J Hoffman, Maria Delivoriapapadopoulos
    Abstract:

    Hypoxia-induced brain cell membrane lipid peroxidation can be caused by free radicals that are produced during hypoxia. Recently, the production of nitric oxide (NO), a free radical, has been shown to be increased during Cerebral hypoxia-ischemia. The present study tested the hypothesis that inhibition of NO synthase (NOS) reduced hypoxia-induced modifications of Na+,K+-ATPase activity, lipid peroxidation, and [3H]MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor in Cerebral Cortical Tissue of newborn piglets. Studies were performed in 26 newborn piglets. Cerebral NOS was inhibited by the i.v. administration of 25 or 50 mg/kg N(omega)-nitro-L-arginine (NNLA) over 30 min. Control animals received normal saline. Six groups of piglets were thus created (normoxia, no NNLA; normoxia + NNLA 25 mg/kg; normoxia + NNLA 50 mg/kg; hypoxia, no NNLA; hypoxia + NNLA 25 mg/kg; hypoxia + NNLA 50 mg/kg). One hour after the start of NNLA or saline infusion, hypoxia was induced by lowering the FiO2 to 0.07 in the three hypoxia groups, whereas in the three other groups normoxia was maintained. After 60 min of hypoxia, the brain was taken out and frozen. NOS activity, Na+,K+-ATPase activity, conjugated dienes, and [3H]MK-801 binding to the NMDA receptor of Cerebral Cortical Tissue were determined. NOS activity was reduced to 34% of its baseline value with NNLA 25 mg/kg, and to 19-27% of its baseline value with NNLA 50 mg/kg, respectively. Administration of NNLA did neither significantly alter the hypoxia-induced production of conjugated dienes, indicating lipid peroxidation nor the decrease of Na+,K+-ATPase activity after hypoxia. [3H]MK-801 binding studies of the NMDA receptor, however, showed that NNLA preserved Bmax and Kd after hypoxia. We conclude that inhibition of NOS does not change the hypoxia-induced decrease of Na+,K+-ATPase activity and production of conjugated dienes in brain cell membranes. Inhibition of NOS preserved the binding of [3H]MK-801 to the NMDA receptor after hypoxia.

  • mechanism of hypoxia induced modification of nmda receptor activity in guinea pig fetus brain 1744
    Pediatric Research, 1997
    Co-Authors: Om P Mishra, Endla K Anday, Santina Zanelli, Maria Delivoriapapadopoulos
    Abstract:

    Our previous studies have shown that hypoxia modifies the NMDA(N-methyl-D-aspartate) receptor in the brain, resulting in decreased Bmax(number of functional receptor ion-channels) and decreased Kd (apparent affinity) and that alteration of the NMDA receptor is related to brain Tissue levels of high energy phosphates (ATP and phosphocreatine). The present study tests the hypothesis that the altered structure of the NMDA receptor during hypoxia is due to dephosphorylation. Guinea pig fetuses were obtained from anesthetized, normoxic (21% oxygen, n=6) and hypoxic (7% oxygen for 60 min, n=6) mothers. Brain Tissue hypoxia in the fetus was documented biochemically by decreased levels of ATP and phosphocreatine. P2 membrane fractions were prepared from fetal Cerebral Cortical Tissue. Both the normoxic and hypoxic membranes were incubated with 10 units of alkaline phosphatase for 30 min. at pH 9.0 NMDA receptor ion channel activity was measured using 3MK-801 binding as an index of receptor function. The results show that in normoxic membranes, enzyme treatment decreased the Bmax from 07.0±0.03 to 0.48±0.02 pmols/mg protein, (p<0.005). The Kd value decreased from 7.5±0.4 to 3.9±0.3 nM (p<0.005). In hypoxic membranes, enzyme treatment had no effect either on the Bmax (0.50±0.021 vs 0.50±0.020 pmols/mg protein, untreated vs treated) or the Kd(4.5±0.3 vs 4.3±0.2 nM, untreated vs treated). Bmax and Kd in untreated hypoxic brain were similar to the results obtained using enzyme treatment leading to dephosphorylation in normoxic brain. The data suggest that, during normoxia, NMDA receptor ion channel function may be regulated by phosphorylation/dephosphorylation and that hypoxia results in dephosphorylation of the NMDA receptor ion channel. We speculate that the increased affinity of the NMDA receptor ion-channel in the dephosphorylated state leads to the initiation of NMDA receptor-mediated events and may be a mechanism of neuronal injury during hypoxia. (Supported by NIH-20337)

Hans Egberts - One of the best experts on this subject based on the ideXlab platform.

  • Cerebral Cortical Tissue damage after hemorrhagic hypotension in near term born lambs
    Pediatric Research, 2006
    Co-Authors: Evelyn Van Den Tweel, Hans Egberts, Jeroen C.w. Hopman, Wim Ruitenbeek, Floris Groenendaal
    Abstract:

    Hypotension reduces Cerebral O(2) supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the Cerebral cortex, as measured with electroCortical brain activity (ECBA), is related to Cerebral Cortical Tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of Cerebral Cortical Tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O(2) supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO(2) and NO(3) (NOx) in plasma, and cGMP in Cortical brain Tissue were determined in both conditions. CSF and brain Tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the Cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, Cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of Cerebral Cortical damage.

  • Cerebral Cortical Tissue damage after hemorrhagic hypotension in near term born lambs
    Pediatric Research, 2006
    Co-Authors: Evelyn Van Den Tweel, Hans Egberts, Jeroen C.w. Hopman, Wim Ruitenbeek, Floris Groenendaal
    Abstract:

    Hypotension reduces Cerebral O(2) supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the Cerebral cortex, as measured with electroCortical brain activity (ECBA), is related to Cerebral Cortical Tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of Cerebral Cortical Tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O(2) supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO(2) and NO(3) (NOx) in plasma, and cGMP in Cortical brain Tissue were determined in both conditions. CSF and brain Tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the Cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, Cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of Cerebral Cortical damage.