Modification of the N-methyl-D-aspartate (NMDA) receptor in the brain of newborn piglets following hyperventilation induced ischemia

Ernest M Graham, Melita Apostolou, Om P. Mishra, Maria Delivoria-Papadopoulos

Research output: Contribution to journalArticle

Abstract

The present study tests the hypothesis that cerebral ischemia induced by severe hypocapnia modifies the N-methyl-D-aspartate (NMDA) receptor/ion channel complex in the cerebral cortical cell membranes of newborn piglets. Studies were performed in six newborn piglets subjected to ischemic hypoxia induced by hyperventilation (PaCO2, 9-11 mmHg) for 1 h. Comparisons were made to a normoxic group on room air (n = 6). Following hyperventilation, phosphocreatine decreased 80%, but ATP remained unchanged. NMDA receptor activation was determined by measuring [3H]MK-801 binding at concentrations varying from 2.5 to 50 nM. Following hyperventilation, B(max) decreased 52% to 0.50 ± 0.04 pmol/mg protein (P = 0.001); however, the K(d) value was unchanged at 7.45 ± 0.79 nM. Spermine and magnesium dependent activation of the NMDA receptor was determined in the hyperventilated and control groups. With spermine concentrations increasing from 2.5 to 50 μM the maximal spermine dependent activation in the normoxic group was 13.7 ± 7.93% which occurred at a concentration of 3.75 ± 1.37 μM. In the hyperventilated group maximal activation was 32.4 ± 23.5% (P = 0.095) at 4.58 ± 2.46 μM (P = ns). With magnesium concentrations increasing from 2.5 to 100 μM the maximal magnesium dependent activation in the normoxic group was 17.0 ± 13.6% which occurred at a concentration of 22.5 ± 6.12 μM. In the hyperventilated group maximal activation was 26.3 ± 14.9% (P = ns) at 4.58 ± 2.92 μM (P <0.0001). These data show that with less severe tissue hypoxia, as evidenced by conservation of ATP, there is less modification of the MMDA receptors. Ischemia induced by hyperventilation leads to an increase in spermine activation of the NMDA receptor, and the NMDA receptor is much more sensitive to magnesium as evidenced by the maximal activation occurring at a significantly lower magnesium concentration. Ischemia induced by hyperventilation modifies the spermine, magnesium, and MK-801 binding sites of the NMDA receptor and may result in increased NMDA receptor mediated neurotoxicity in the newborn brain.

Original languageEnglish (US)
Pages (from-to)29-32
Number of pages4
JournalNeuroscience Letters
Volume218
Issue number1
DOIs
StatePublished - Oct 25 1996
Externally publishedYes

Fingerprint

Hyperventilation
N-Methyl-D-Aspartate Receptors
Spermine
Magnesium
Ischemia
Brain
Dizocilpine Maleate
Adenosine Triphosphate
Hypocapnia
Phosphocreatine
Brain Ischemia
Ion Channels
Binding Sites
Air
Cell Membrane
Control Groups

Keywords

  • Hyperventilation
  • Ischemia
  • Magnesium
  • MK-801
  • N-Methyl-D-aspartate receptor
  • Spermine

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Modification of the N-methyl-D-aspartate (NMDA) receptor in the brain of newborn piglets following hyperventilation induced ischemia. / Graham, Ernest M; Apostolou, Melita; Mishra, Om P.; Delivoria-Papadopoulos, Maria.

In: Neuroscience Letters, Vol. 218, No. 1, 25.10.1996, p. 29-32.

Research output: Contribution to journalArticle

Graham, Ernest M ; Apostolou, Melita ; Mishra, Om P. ; Delivoria-Papadopoulos, Maria. / Modification of the N-methyl-D-aspartate (NMDA) receptor in the brain of newborn piglets following hyperventilation induced ischemia. In: Neuroscience Letters. 1996 ; Vol. 218, No. 1. pp. 29-32.
@article{72d9c9d421a840faa4034e8bdf6c742b,
title = "Modification of the N-methyl-D-aspartate (NMDA) receptor in the brain of newborn piglets following hyperventilation induced ischemia",
abstract = "The present study tests the hypothesis that cerebral ischemia induced by severe hypocapnia modifies the N-methyl-D-aspartate (NMDA) receptor/ion channel complex in the cerebral cortical cell membranes of newborn piglets. Studies were performed in six newborn piglets subjected to ischemic hypoxia induced by hyperventilation (PaCO2, 9-11 mmHg) for 1 h. Comparisons were made to a normoxic group on room air (n = 6). Following hyperventilation, phosphocreatine decreased 80{\%}, but ATP remained unchanged. NMDA receptor activation was determined by measuring [3H]MK-801 binding at concentrations varying from 2.5 to 50 nM. Following hyperventilation, B(max) decreased 52{\%} to 0.50 ± 0.04 pmol/mg protein (P = 0.001); however, the K(d) value was unchanged at 7.45 ± 0.79 nM. Spermine and magnesium dependent activation of the NMDA receptor was determined in the hyperventilated and control groups. With spermine concentrations increasing from 2.5 to 50 μM the maximal spermine dependent activation in the normoxic group was 13.7 ± 7.93{\%} which occurred at a concentration of 3.75 ± 1.37 μM. In the hyperventilated group maximal activation was 32.4 ± 23.5{\%} (P = 0.095) at 4.58 ± 2.46 μM (P = ns). With magnesium concentrations increasing from 2.5 to 100 μM the maximal magnesium dependent activation in the normoxic group was 17.0 ± 13.6{\%} which occurred at a concentration of 22.5 ± 6.12 μM. In the hyperventilated group maximal activation was 26.3 ± 14.9{\%} (P = ns) at 4.58 ± 2.92 μM (P <0.0001). These data show that with less severe tissue hypoxia, as evidenced by conservation of ATP, there is less modification of the MMDA receptors. Ischemia induced by hyperventilation leads to an increase in spermine activation of the NMDA receptor, and the NMDA receptor is much more sensitive to magnesium as evidenced by the maximal activation occurring at a significantly lower magnesium concentration. Ischemia induced by hyperventilation modifies the spermine, magnesium, and MK-801 binding sites of the NMDA receptor and may result in increased NMDA receptor mediated neurotoxicity in the newborn brain.",
keywords = "Hyperventilation, Ischemia, Magnesium, MK-801, N-Methyl-D-aspartate receptor, Spermine",
author = "Graham, {Ernest M} and Melita Apostolou and Mishra, {Om P.} and Maria Delivoria-Papadopoulos",
year = "1996",
month = "10",
day = "25",
doi = "10.1016/S0304-3940(96)13114-1",
language = "English (US)",
volume = "218",
pages = "29--32",
journal = "Neuroscience Letters",
issn = "0304-3940",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - Modification of the N-methyl-D-aspartate (NMDA) receptor in the brain of newborn piglets following hyperventilation induced ischemia

AU - Graham, Ernest M

AU - Apostolou, Melita

AU - Mishra, Om P.

AU - Delivoria-Papadopoulos, Maria

PY - 1996/10/25

Y1 - 1996/10/25

N2 - The present study tests the hypothesis that cerebral ischemia induced by severe hypocapnia modifies the N-methyl-D-aspartate (NMDA) receptor/ion channel complex in the cerebral cortical cell membranes of newborn piglets. Studies were performed in six newborn piglets subjected to ischemic hypoxia induced by hyperventilation (PaCO2, 9-11 mmHg) for 1 h. Comparisons were made to a normoxic group on room air (n = 6). Following hyperventilation, phosphocreatine decreased 80%, but ATP remained unchanged. NMDA receptor activation was determined by measuring [3H]MK-801 binding at concentrations varying from 2.5 to 50 nM. Following hyperventilation, B(max) decreased 52% to 0.50 ± 0.04 pmol/mg protein (P = 0.001); however, the K(d) value was unchanged at 7.45 ± 0.79 nM. Spermine and magnesium dependent activation of the NMDA receptor was determined in the hyperventilated and control groups. With spermine concentrations increasing from 2.5 to 50 μM the maximal spermine dependent activation in the normoxic group was 13.7 ± 7.93% which occurred at a concentration of 3.75 ± 1.37 μM. In the hyperventilated group maximal activation was 32.4 ± 23.5% (P = 0.095) at 4.58 ± 2.46 μM (P = ns). With magnesium concentrations increasing from 2.5 to 100 μM the maximal magnesium dependent activation in the normoxic group was 17.0 ± 13.6% which occurred at a concentration of 22.5 ± 6.12 μM. In the hyperventilated group maximal activation was 26.3 ± 14.9% (P = ns) at 4.58 ± 2.92 μM (P <0.0001). These data show that with less severe tissue hypoxia, as evidenced by conservation of ATP, there is less modification of the MMDA receptors. Ischemia induced by hyperventilation leads to an increase in spermine activation of the NMDA receptor, and the NMDA receptor is much more sensitive to magnesium as evidenced by the maximal activation occurring at a significantly lower magnesium concentration. Ischemia induced by hyperventilation modifies the spermine, magnesium, and MK-801 binding sites of the NMDA receptor and may result in increased NMDA receptor mediated neurotoxicity in the newborn brain.

AB - The present study tests the hypothesis that cerebral ischemia induced by severe hypocapnia modifies the N-methyl-D-aspartate (NMDA) receptor/ion channel complex in the cerebral cortical cell membranes of newborn piglets. Studies were performed in six newborn piglets subjected to ischemic hypoxia induced by hyperventilation (PaCO2, 9-11 mmHg) for 1 h. Comparisons were made to a normoxic group on room air (n = 6). Following hyperventilation, phosphocreatine decreased 80%, but ATP remained unchanged. NMDA receptor activation was determined by measuring [3H]MK-801 binding at concentrations varying from 2.5 to 50 nM. Following hyperventilation, B(max) decreased 52% to 0.50 ± 0.04 pmol/mg protein (P = 0.001); however, the K(d) value was unchanged at 7.45 ± 0.79 nM. Spermine and magnesium dependent activation of the NMDA receptor was determined in the hyperventilated and control groups. With spermine concentrations increasing from 2.5 to 50 μM the maximal spermine dependent activation in the normoxic group was 13.7 ± 7.93% which occurred at a concentration of 3.75 ± 1.37 μM. In the hyperventilated group maximal activation was 32.4 ± 23.5% (P = 0.095) at 4.58 ± 2.46 μM (P = ns). With magnesium concentrations increasing from 2.5 to 100 μM the maximal magnesium dependent activation in the normoxic group was 17.0 ± 13.6% which occurred at a concentration of 22.5 ± 6.12 μM. In the hyperventilated group maximal activation was 26.3 ± 14.9% (P = ns) at 4.58 ± 2.92 μM (P <0.0001). These data show that with less severe tissue hypoxia, as evidenced by conservation of ATP, there is less modification of the MMDA receptors. Ischemia induced by hyperventilation leads to an increase in spermine activation of the NMDA receptor, and the NMDA receptor is much more sensitive to magnesium as evidenced by the maximal activation occurring at a significantly lower magnesium concentration. Ischemia induced by hyperventilation modifies the spermine, magnesium, and MK-801 binding sites of the NMDA receptor and may result in increased NMDA receptor mediated neurotoxicity in the newborn brain.

KW - Hyperventilation

KW - Ischemia

KW - Magnesium

KW - MK-801

KW - N-Methyl-D-aspartate receptor

KW - Spermine

UR - http://www.scopus.com/inward/record.url?scp=0030601806&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030601806&partnerID=8YFLogxK

U2 - 10.1016/S0304-3940(96)13114-1

DO - 10.1016/S0304-3940(96)13114-1

M3 - Article

C2 - 8939473

AN - SCOPUS:0030601806

VL - 218

SP - 29

EP - 32

JO - Neuroscience Letters

JF - Neuroscience Letters

SN - 0304-3940

IS - 1

ER -