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Mitochondrial nitric oxide mediates decreased vulnerability of hippocampal neurons from immature animals to NMDA.

Mitochondrial membrane potential ( Delta psi sub(m))-dependent Ca super(2+) uptake plays a central role in neurodegeneration after NMDA receptor activation. NMDA-induced Delta psi sub(m) dissipation increases during postnatal development, coincident with increasing vulnerability to NMDA. NMDA recept... Full description

Journal Title: The Journal of neuroscience : the official journal of the Society for Neuroscience July 13, 2005, Vol.25(28), pp.6561-6575
Main Author: Marks, Jeremy D
Other Authors: Boriboun, Chan , Wang, Janice
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1529-2401
Link: http://search.proquest.com/docview/68026070/?pq-origsite=primo
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title: Mitochondrial nitric oxide mediates decreased vulnerability of hippocampal neurons from immature animals to NMDA.
format: Article
creator:
  • Marks, Jeremy D
  • Boriboun, Chan
  • Wang, Janice
subjects:
  • Animals–Metabolism
  • Animals, Newborn–Pharmacology
  • Calcium–Drug Effects
  • Carbonyl Cyanide P-Trifluoromethoxyphenylhydrazone–Physiology
  • Cells, Cultured–Analogs & Derivatives
  • Clonazepam–Pharmacology
  • Hippocampus–Cytology
  • Indazoles–Growth & Development
  • Ion Transport–Pharmacology
  • Mitochondria–Enzymology
  • N-Methylaspartate–Physiology
  • Ng-Nitroarginine Methyl Ester–Pharmacology
  • Nerve Degeneration–Toxicity
  • Nerve Tissue Proteins–Pharmacology
  • Neurons–Physiology
  • Nitric Oxide–Drug Effects
  • Nitric Oxide Synthase Type I–Metabolism
  • Oxadiazoles
ispartof: The Journal of neuroscience : the official journal of the Society for Neuroscience, July 13, 2005, Vol.25(28), pp.6561-6575
description: Mitochondrial membrane potential ( Delta psi sub(m))-dependent Ca super(2+) uptake plays a central role in neurodegeneration after NMDA receptor activation. NMDA-induced Delta psi sub(m) dissipation increases during postnatal development, coincident with increasing vulnerability to NMDA. NMDA receptor activation also produces nitric oxide (NO), which can inhibit mitochondrial respiration, dissipating Delta psi sub(m). Because Delta psi sub(m) dissipation reduces mitochondrial Ca super(2+) uptake, we hypothesized that NO mediates the NMDA-induced Delta psi sub(m) dissipation in immature neurons, underlying their decreased vulnerability to excitotoxicity. Using hippocampal neurons cultured from 5- and 19-d-old rats, we measured NMDA-induced changes in [Ca super(2+)] sub(cytosol), Delta psi sub(m), NO, and [Ca super(2+)] sub(mito). In postnatal day 5 (P5) neurons, NMDA mildly dissipated Delta psi sub(m) in a NO synthase (NOS)-dependent manner and increased NO. The NMDA-induced NO increase was abolished with carbonyl cyanide 4-(trifluoromethoxy)phenyl-hydrazone and regulated by [Ca super(2+)] sub(mito). Mitochondrial Ca super(2+) uptake inhibition prevented the NO increase, whereas inhibition of mitochondrial Ca super(2+) extrusion increased it. Consistent with this mitochondrial regulation, NOS and cytochrome oxidase immunoreactivity demonstrated mitochondrial localization of NOS. Furthermore, NOS blockade increased mitochondrial Ca super(2+) uptake during NMDA. Finally, at physiologic O sub(2) tensions (3% O sub(2)), NMDA had little effect on survival of P5 neurons, but NOS blockade during NMDA markedly worsened survival, demonstrating marked neuroprotection by mitochondrial NO. In P19 neurons, NMDA dissipated Delta psi sub(m) in an NO-insensitive manner. NMDA-induced NO production was not regulated by Delta psi sub(m), and NOS immunoreactivity was cytosolic, without mitochondrial localization. NOS blockade also protected P19 neurons from NMDA. These data demonstrate that mitochondrial NOS mediates much of the decreased vulnerability to NMDA in immature hippocampal neurons and that cytosolic NOS contributes to NMDA toxicity in mature neurons.
language: eng
source:
identifier: E-ISSN: 1529-2401
fulltext: fulltext
issn:
  • 15292401
  • 1529-2401
url: Link


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titleMitochondrial nitric oxide mediates decreased vulnerability of hippocampal neurons from immature animals to NMDA.
creatorMarks, Jeremy D ; Boriboun, Chan ; Wang, Janice
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subjectAnimals–Metabolism ; Animals, Newborn–Pharmacology ; Calcium–Drug Effects ; Carbonyl Cyanide P-Trifluoromethoxyphenylhydrazone–Physiology ; Cells, Cultured–Analogs & Derivatives ; Clonazepam–Pharmacology ; Hippocampus–Cytology ; Indazoles–Growth & Development ; Ion Transport–Pharmacology ; Mitochondria–Enzymology ; N-Methylaspartate–Physiology ; Ng-Nitroarginine Methyl Ester–Pharmacology ; Nerve Degeneration–Toxicity ; Nerve Tissue Proteins–Pharmacology ; Neurons–Physiology ; Nitric Oxide–Drug Effects ; Nitric Oxide Synthase Type I–Metabolism ; Oxadiazoles
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descriptionMitochondrial membrane potential ( Delta psi sub(m))-dependent Ca super(2+) uptake plays a central role in neurodegeneration after NMDA receptor activation. NMDA-induced Delta psi sub(m) dissipation increases during postnatal development, coincident with increasing vulnerability to NMDA. NMDA receptor activation also produces nitric oxide (NO), which can inhibit mitochondrial respiration, dissipating Delta psi sub(m). Because Delta psi sub(m) dissipation reduces mitochondrial Ca super(2+) uptake, we hypothesized that NO mediates the NMDA-induced Delta psi sub(m) dissipation in immature neurons, underlying their decreased vulnerability to excitotoxicity. Using hippocampal neurons cultured from 5- and 19-d-old rats, we measured NMDA-induced changes in [Ca super(2+)] sub(cytosol), Delta psi sub(m), NO, and [Ca super(2+)] sub(mito). In postnatal day 5 (P5) neurons, NMDA mildly dissipated Delta psi sub(m) in a NO synthase (NOS)-dependent manner and increased NO. The NMDA-induced NO increase was abolished with carbonyl cyanide 4-(trifluoromethoxy)phenyl-hydrazone and regulated by [Ca super(2+)] sub(mito). Mitochondrial Ca super(2+) uptake inhibition prevented the NO increase, whereas inhibition of mitochondrial Ca super(2+) extrusion increased it. Consistent with this mitochondrial regulation, NOS and cytochrome oxidase immunoreactivity demonstrated mitochondrial localization of NOS. Furthermore, NOS blockade increased mitochondrial Ca super(2+) uptake during NMDA. Finally, at physiologic O sub(2) tensions (3% O sub(2)), NMDA had little effect on survival of P5 neurons, but NOS blockade during NMDA markedly worsened survival, demonstrating marked neuroprotection by mitochondrial NO. In P19 neurons, NMDA dissipated Delta psi sub(m) in an NO-insensitive manner. NMDA-induced NO production was not regulated by Delta psi sub(m), and NOS immunoreactivity was cytosolic, without mitochondrial localization. NOS blockade also protected P19 neurons from NMDA. These data demonstrate that mitochondrial NOS mediates much of the decreased vulnerability to NMDA in immature hippocampal neurons and that cytosolic NOS contributes to NMDA toxicity in mature neurons.
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