Cerebral blood flow thresholds for mRNA synthesis after focal ischemia and the effect of MK-801

Tatsushi Kamiya, Michael Jacewicz, Thaddeus Nowak, William A. Pulsinelli

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background and Purpose - MK-801 is a noncompetitive antagonist of N-methyl-D-aspartate subtype glutamate receptors with protective efficacy in experimental stroke. This study examined the impact of MK-801 on cerebral blood flow (CBF) and its relationship to gene expression changes during focal ischemia. Methods - Spontaneously hypertensive rats were subjected to surgical occlusion of the middle cerebral artery and ipsilateral common carotid artery after 30 minutes pretreatment with 5 mg/kg MK-801 or saline vehicle. After 2.5 hours of ischemia, regional CBF was evaluated by [14C]iodoantipyrine autoradiography and compared with distributions of gene expression changes evaluated by in situ hybridization detection of mRNAs encoding several immediate-early genes and the stress protein, hsp72. Results - MK-801 increased CBF in contralateral cortex from 93±15 to 187±37 mL/100 g per minute and produced a significant 25% reduction in the volume of ischemic cortex ipsilateral to occlusion. The extent of cortex failing to express inducible mRNAs correspondingly decreased, but the CBF threshold for mRNA synthesis remained unchanged (25 to 30 mL/100 g per minute). Widespread immediate-early gene expression in the neocortex became restricted to periinfarct regions after MK-801 treatment, and hybridization patterns in the striatum and hippocampus reflected the altered topography of cortical activation after drug treatment. Conclusions - MK-801 alters ischemia-induced gene expression by 2 distinct mechanisms. Generalized increases in CBF reduce the volume of cortex falling below ischemic injury thresholds, protecting tissue and facilitating transcription of inducible genes proximal to the ischemic focus. In addition, MK-801 attenuates the signals that induce expression of immediate-early genes in cortical and subcortical regions remote from the middle cerebral artery territory.

Original languageEnglish (US)
Pages (from-to)2463-2467
Number of pages5
JournalStroke
Volume36
Issue number11
DOIs
StatePublished - Nov 1 2005

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Cerebrovascular Circulation
Dizocilpine Maleate
Ischemia
Messenger RNA
Immediate-Early Genes
Gene Expression
Middle Cerebral Artery Infarction
Common Carotid Artery
Neocortex
Regional Blood Flow
Middle Cerebral Artery
Glutamate Receptors
Inbred SHR Rats
N-Methylaspartate
Heat-Shock Proteins
Autoradiography
In Situ Hybridization
Hippocampus
Stroke

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Cerebral blood flow thresholds for mRNA synthesis after focal ischemia and the effect of MK-801. / Kamiya, Tatsushi; Jacewicz, Michael; Nowak, Thaddeus; Pulsinelli, William A.

In: Stroke, Vol. 36, No. 11, 01.11.2005, p. 2463-2467.

Research output: Contribution to journalArticle

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abstract = "Background and Purpose - MK-801 is a noncompetitive antagonist of N-methyl-D-aspartate subtype glutamate receptors with protective efficacy in experimental stroke. This study examined the impact of MK-801 on cerebral blood flow (CBF) and its relationship to gene expression changes during focal ischemia. Methods - Spontaneously hypertensive rats were subjected to surgical occlusion of the middle cerebral artery and ipsilateral common carotid artery after 30 minutes pretreatment with 5 mg/kg MK-801 or saline vehicle. After 2.5 hours of ischemia, regional CBF was evaluated by [14C]iodoantipyrine autoradiography and compared with distributions of gene expression changes evaluated by in situ hybridization detection of mRNAs encoding several immediate-early genes and the stress protein, hsp72. Results - MK-801 increased CBF in contralateral cortex from 93±15 to 187±37 mL/100 g per minute and produced a significant 25{\%} reduction in the volume of ischemic cortex ipsilateral to occlusion. The extent of cortex failing to express inducible mRNAs correspondingly decreased, but the CBF threshold for mRNA synthesis remained unchanged (25 to 30 mL/100 g per minute). Widespread immediate-early gene expression in the neocortex became restricted to periinfarct regions after MK-801 treatment, and hybridization patterns in the striatum and hippocampus reflected the altered topography of cortical activation after drug treatment. Conclusions - MK-801 alters ischemia-induced gene expression by 2 distinct mechanisms. Generalized increases in CBF reduce the volume of cortex falling below ischemic injury thresholds, protecting tissue and facilitating transcription of inducible genes proximal to the ischemic focus. In addition, MK-801 attenuates the signals that induce expression of immediate-early genes in cortical and subcortical regions remote from the middle cerebral artery territory.",
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