Elsevier

Experimental Neurology

Volume 160, Issue 2, December 1999, Pages 317-332
Experimental Neurology

Regular Article
Prolonged Induction of Neuronal NOS Expression and Activity Following Cortical Spreading Depression (SD): Implications for SD- and NO-Mediated Neuroprotection

https://doi.org/10.1006/exnr.1999.7218Get rights and content

Abstract

Cortical spreading depression (CSD) is associated with various short- and long-term physiological and neurochemical changes and has been shown to confer an increased susceptibility to accompanying ischemic injury or provide protection against a subsequent experimental ischemia. Nitric oxide is involved in the processes of ischemic injury and under certain conditions mediates cellular protection. To investigate the possibility that CSD-induced alterations in nitric oxide synthase (NOS) expression and activity occur and might be associated with the time-dependent enhancement or prevention by CSD of ischemic damage, this study examined the spatiotemporal changes in nNOS expression and activity in cerebral cortex following CSD. Anesthetized rats had unilateral CSD induced by a 10-min topical application of KCl and were killed at various times thereafter. CSD increased both nNOS mRNA and protein levels throughout layers II–III of cortex. nNOS mRNA in the affected neocortex was significantly increased by 30–90% at 2, 7, and 14 days (P  0.05) compared with contralateral levels, but was not significantly above control values at 1–6 h, 1 day, and 28 days after CSD induction. Levels of [3H]-l-NG-nitroarginine binding to NOS were increased by 40–170% 7, 14, and 28 days (P  0.01) after CSD in a similar, but delayed, profile to nNOS mRNA. Levels of nNOS-immunoreactivity were also increased in both neurons and astrocytes of ipsilateral cortex 7 and 14 days after CSD—confirmed by double-immunofluorescence localization. Ex vivo NOS activity in layers I–III of ipsilateral cortex was also increased by 30–50% (P  0.01) at 7 and 14 days after CSD, times coincident with reported maximal ischemic protection. These results demonstrate that nNOS is up-regulated by cellular depolarization/depression occurring during CSD, or by resultant stimuli and suggest that “CSD-conditioned” cortex may be capable of producing appropriate levels of NO to mediate or contribute to protective/adaptive responses to subsequent physical ischemic injury.

References (79)

  • E.J. Kidd et al.

    Autoradiographic distribution of [3H]l-NG-nitro-arginine binding in rat brain

    Neuropharmacology

    (1995)
  • Z. Kokaia et al.

    Rapid increase of BDNF mRNA levels in cortical neurons following spreading depression: Regulation by glutamatergic mechanisms independent of seizure activity

    Mol. Brain. Res.

    (1993)
  • S.Z. Lei et al.

    Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex

    Neuron

    (1992)
  • G. Lonart et al.

    Nitric oxide induces neurotransmitter release from hippocampal slices

    Eur. J. Pharmacol.

    (1992)
  • O. Manzoni et al.

    Nitric oxide-induced blockade of NMDA receptors

    Neuron

    (1992)
  • M.G. Mohaupt et al.

    Differential expression and induction of mRNAs encoding two inducible nitric oxide synthases in rat kidney

    Kidney Int.

    (1994)
  • M. Nedergaard et al.

    Spreading depression is not associated with neuronal injury in the normal brain

    Brain Res.

    (1988)
  • J.P. Nowicki et al.

    Nitric oxide mediates neuronal death after focal cerebral ischemia in the mouse

    Eur. J. Pharmacol.

    (1991)
  • S.J. Read et al.

    Nitric oxide does not mediate cerebral blood flow changes during cortical spreading depression in the anaesthetised rat

    Neurosci. Lett.

    (1998)
  • S.J. Read et al.

    The dynamics of nitric oxide release measured directly and in real time following repeated waves of cortical spreading depression in the anaesthetised cat

    Neurosci. Lett.

    (1997)
  • J. Segieth et al.

    Nitric oxide regulates excitatory amino acid release in a biphasic manner in freely moving rats

    Neurosci. Lett.

    (1995)
  • P.-J. Shen et al.

    Differential spatiotemporal alterations in adrenoceptor mRNAs and binding in cerebral cortex following spreading depression: Selective and prolonged up-regulation of α1B-adrenoceptors

    Exp. Neurol.

    (1998)
  • R.J. Thompson et al.

    PGP9.5—a new marker for vertebrate neurons and neuroendocrine cells

    Brain Res.

    (1983)
  • H.J. Ulmer et al.

    Effects of nitric oxide on the retinal spreading depression

    Brain Res.

    (1995)
  • J. Wu et al.

    Evidence for involvement of the neuronal isoform of nitric oxide synthase during induction of long-term potentiation and long-term depression in the rat dentate gyrus in vitro

    Neuroscience

    (1997)
  • W. Wu et al.

    Increased expression of nitric oxide synthase in hypothalamic neuronal regeneration

    Exp. Neurol.

    (1993)
  • H. Yanamoto et al.

    Infarct tolerance against temporary focal ischemia following spreading depression in rat brain

    Brain Res.

    (1998)
  • Y. Yui et al.

    Purification of nitric oxide synthase from rat macrophages

    J. Biol. Chem.

    (1991)
  • H.-J. Bidmon et al.

    Transient changes in the presence of nitric oxide synthases and nitrotyrosine immunoreactivity after focal cortical lesions

    Neuroscience

    (1998)
  • D.S. Bredt et al.

    Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase

    Nature

    (1991)
  • D.S. Bredt et al.

    Isolation of nitric oxide synthase, a calmodulin-requiring enzyme

    Proc. Natl. Acad. Sci. USA

    (1990)
  • T.C.D. Burazin et al.

    Localization of NO synthase in rat brain by [3H]L-NG-nitro-arginine autoradiography

    NeuroReport

    (1995)
  • E. Busch et al.

    Potassium-induced cortical spreading depressions during focal cerebral ischemia in rats: Contribution to lesion growth assessed by diffusion-weighted NMR and biochemical imaging

    J. Cereb. Blood Flow Metab.

    (1996)
  • A.O. Caggiano et al.

    Neuronal nitric oxide synthase expression is induced in neocortical astrocytes after spreading depression

    J. Cereb. Blood Flow Metab.

    (1998)
  • W.D. Dietrich et al.

    Photothrombotic infarction triggers multiple episodes of cortical spreading depression in distant brain regions

    J. Cereb. Blood Flow Metab.

    (1994)
  • J.L. Dinerman et al.

    Endothelial nitric oxide synthase localized to hippocampal pyramidal cells: Implications for synaptic plasticity

    Proc. Natl. Acad. Sci. USA

    (1994)
  • L.F. Eng

    The glial fibrillary acidic (GFA) protein

  • O.W. Griffith et al.

    Nitric oxide synthases: Properties and catalytic mechanisms

    Annu. Rev. Physiol.

    (1995)
  • R. Guevara-Guzman et al.

    Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP

    J. Neurochem.

    (1994)
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