Transient MRI-detected water apparent diffusion coefficient reduction correlates with c-fos mRNA but not hsp70 mRNA induction during focal cerebral ischemia in rats

doi:10.1016/S0006-8993(99)01631-5

Brain Research

Volume 839, Issue 1, 21 August 1999, Pages 7-22

https://doi.org/10.1016/S0006-8993(99)01631-5 Get rights and content

Abstract

Cerebral ischemia induces immediate early genes such as c-fos and stress genes such as hsp70. In this study, the spatial relationships between c-fos and hsp70 mRNA expression and changes detectable with diffusion and perfusion magnetic resonance (MR) imaging were examined. The middle cerebral artery (MCA) of young adult rats was occluded for 30 or 60 min. Diffusion MR (D-MR) images were acquired continuously during the ischemic period and dysprosium-contrast perfusion (P-MR) images were acquired at the end of the ischemic period. C-fos and hsp70 mRNA expression were examined with in situ hybridization. The most significant finding of this work was that for both durations of ischemia, c-fos induction was observed in cortical and sub-cortical regions exhibiting a transient reduction in the apparent diffusion coefficient of water (ADC). Transients which occurred on a time scale of 3 min may have been caused by spreading depression. Those occurring on a 10-min time scale may have been caused by an initial reduction in blood flow with occlusion that was followed by an ischemia-induced increase in collateral blood flow. P-MR imaging showed that perfusion in c-fos positive regions was higher than in regions with persistently reduced ADC. Hsp70 induction did not correlate with transient ADC reduction. It was induced in the MCA territory in regions showing persistent ADC changes, with induction being greatest at the periphery of these regions. It was also induced in regions that exhibited both spontaneous reversal of the diffusion changes and decreased perfusion.

Introduction

Focal cerebral ischemia produces changes in gene transcription and translation that are related to the extent of blood flow reduction. While total protein synthesis is generally reduced with ischemia [46], some genes, including the c-fos immediate early gene 2, 29, 35, 67, 73 and the 70 kD heat shock stress gene (hsp70), are induced with ischemia 9, 20, 29, 30, 31, 39, 56, 57, 69. Diffusion magnetic resonance (D-MR) imaging detects changes in water diffusion that are likely related to cellular edema [68] and dysprosium-contrast perfusion (P-MR) imaging allows non-invasive determination of regional blood flow [72]. The aim of this study was to examine the spatial relationship between c-fos and hsp70 mRNA expression and changes detectable with diffusion and perfusion MR imaging during middle cerebral artery (MCA) occlusion in rats.

C-fos protein, when dimerized to a jun protein family member, binds to AP1 sites on promoters of a variety of target genes that may play a role in neuronal plasticity 11, 35, 50. MCA occlusion induces c-fos mRNA in cortical regions within the MCA territory 2, 31, 67. C-fos is also induced in medial dorsal cortex and cingulate cortex of the ischemic hemisphere where little or no blood flow reduction occurs 2, 29, 67, 73. Such c-fos expression is believed to be caused by spreading depression, which is known to occur during acute focal ischemia [53]. Support for this belief stems from a number of experimental findings. Ischemia-induced c-fos transcription can be inhibited by the NMDA receptor antagonist MK-801 (dizocilpine maleate), 10, 16, 30, which is known to inhibit spreading depression during ischemia [17]. In addition, spreading depression initiated by cortical application of potassium chloride induces c-fos and such induction can also be blocked by MK-801 [23].

Heat shock proteins (HSPs) are molecular “chaperones” that bind to other proteins to shepherd them across membranes and direct them to specific locations within a cell 44, 51. Certain HSPs also bind to denatured proteins in order to prevent further denaturation and to promote renaturation 40, 44, 45. Several injurious stimuli can induce hsp70 expression, including excitotoxin exposure 20, 69, ischemia 20, 69, 70, trauma [5] and elevated body temperature [47]. Induction of heat shock genes is mediated by denatured proteins 3, 59 and HSPs provide protection against subsequent injury 27, 33, 45, 58. During acute MCA occlusion, hsp70 expression in the ischemic core is modest and limited to endothelial cells; it is markedly induced in neurons and glia at the lesion periphery 30, 31, 32.

Diffusion-weighted magnetic resonance imaging is a sensitive indicator of early ischemia [52]. Hyper-intensity on D-MR images reflects a decrease in the apparent diffusion coefficient of water (ADC). The decrease in ADC is reversible with reperfusion [49] and if the duration of occlusion is sufficiently short, some regions with intra-ischemic ADC reduction remain viable 42, 48. Some of the ADC reduction is probably caused by energy failure 4, 8, 13 that results in sodium and chloride influx and osmotic cell swelling 1, 71. The shift of tissue water from the more mobile extracellular space to the less mobile intracellular space and the increased tortuosity of the extracellular space results in reduced ADC 54, 55.

Spreading depression has been shown to produce a transient reduction in ADC that propagates away from the site of stimulation 6, 7, 37. The reduction is believed to be caused by the shift of water from the extracellular space to the intracellular space [25]. The water shift is osmotically driven and is the direct result of an influx of sodium and chloride that occurs with depolarization.

P-MR imaging with a susceptibility contrast agent [72] has been used to examine regional blood flow during acute cerebral ischemia 12, 36. This method has been used to demonstrate graded levels of perfusion deficit in dorsal aspects of cortex during acute MCA occlusion in rats [61].

In this study, the relationships between induction of c-fos and hsp70 mRNA and changes detectable with echo-planar D-MR and P-MR imaging were examined. Rats subjected to either 30 or 60-min MCA occlusion were examined with diffusion imaging throughout the ischemic period. Perfusion images were acquired at the end of the ischemic period following a bolus injection of dysprosium diethylene triaminepentaacetic acid bis (methyl amide) (DyDTPA-BMA). The experiments tested the following hypotheses. (1) C-fos mRNA is induced in the ischemic hemisphere in regions exhibiting transient but not permanent ADC reduction. (2) C-fos positive regions of cortex have higher blood flow levels than those of the central ischemic region. (3) hsp70 mRNA is induced in regions that exhibit permanent ADC reduction.

Section snippets

Animal model

Male Sprague–Dawley rats weighing 260–320 g were used. They were given free access to food and water prior to use in experiments. Anesthesia was induced with 3% isoflurane in a closed chamber and maintained with 1.5% isoflurane (both in 70/30 N₂O/O₂) through an intra-tracheal 16-gauge Teflon® tube. A rodent ventilator (Model 683, Harvard Instruments, South Natick, MA) was used for mechanical ventilation; respiratory adjustments were made to maintain normal arterial blood gas levels. Just before

Physiological data

Blood pressure and blood gas results for the pre- and intra-ischemic periods are summarized in Table 1. No significant difference was observed between the two time points or between the two groups.

30-min MCA occlusion images and maps

A typical series of ADC maps acquired during a 30-min ischemic period are shown in Fig. 1. The colored areas indicate regions with significantly reduced ADC relative to the average ADC value of the non-ischemic hemisphere. The ADC reduction in the ischemic hemisphere ranged from 20% (red) to 45%

Discussion

The most significant finding of this work was the close spatial correspondence between c-fos positive regions and regions exhibiting transient ADC reduction. This finding is consistent with the first hypothesis of this study. Two different durations for the transients were observed, a brief one and a more prolonged one. The brief transient changes lasted approximately 3 min and were probably due to spreading depression. Support for this belief stems from the observation that many of these

Conclusions

The most significant finding of this work was a close spatial relationship between c-fos mRNA induction and transient ADC reduction. This finding supports the belief that brief transient ADC reduction at the periphery of a focal ischemic lesion is the result of spreading depression. C-fos was also induced by longer transient ADC reductions. These transients may have resulted from an initial decrease in blood flow with occlusion that was followed by an ischemia-induced increase in collateral

Acknowledgements

This work was supported by grants from the National Institute for Neurological Disorders and Stroke, NS22022 (PRW), NS14543 (FRS), and NS28167 (FRS). We thank Mr. Leo Benjamin, Ms. Theresa Marsh and Ms. Karen Solway for help with in situ hybridization studies and Dr. Michael F. Wendland for assistance with MRI experiments.

References (73)

K.L. Allen et al.
Early changes in cerebral sodium distribution following ischaemia monitored by $^{23} Na$ magnetic resonance imaging
Magn. Reson. Imaging
(1994)
I.R. Brown et al.
Induction of a heat shock gene at the site of tissue injury in the rat brain
Neuron
(1989)
J.A. Detre et al.
Correlation of diffusion MRI and heat shock protein in a rat embolic stroke model
J. Neurol. Sci.
(1997)
M.F. Gonzalez et al.
Heat shock proteins as markers of neural injury
Brain Res. Mol. Brain Res.
(1989)
D.G. Herrera et al.
N-methyl-D-aspartate receptors mediate activation of the c-fos proto-oncogene in a model of brain injury
Neuroscience
(1990)
D.G. Herrera et al.
Application of potassium chloride to the brain surface induces the c-fos proto-oncogene: reversal by MK-801
Brain Res.
(1990)
D.G. Herrera et al.
Activation of c-fos in the brain
Prog. Neurobiol.
(1996)
H. Kinouchi et al.
MK-801 inhibits the induction of immediate early genes in cerebral cortex, thalamus, and hippocampus, but not in substantia nigra following middle cerebral artery occlusion
Neurosci. Lett.
(1994)
H. Kinouchi et al.
Induction of heat shock hsp70 mRNA and HSP70 kDa protein in neurons in the `penumbra' following focal cerebral ischemia in the rat
Brain Res.
(1993)
Y. Li et al.
Neuronal survival is associated with 72-kDa heat shock protein expression after transient middle cerebral artery occlusion in the rat
J. Neurol. Sci.
(1993)

S. Lindquist

Heat-shock proteins and stress tolerance in microorganisms

Curr. Opin. Genet. Dev.

(1992)

A. Mancuso et al.

Prediction of delayed ischemic injury with diffusion-weighted MRI following temporary middle cerebral artery occlusion in rats

Brain Res.

(1997)

J.I. Morgan et al.

Immediate-early genes: ten years on

Trends Neurosci.

(1995)

H.R. Pelham

Speculations on the functions of the major heat shock and glucose-regulated proteins

Cell

(1986)

J.W. Sharp et al.

The NMDA receptor mediates cortical induction of fos and fos-related antigens following cortical injury

Exp. Neurol.

(1990)

Y. Uemura et al.

Focal ischemia in rats causes time-dependent expression of c-fos protein immunoreactivity in widespread regions of ipsilateral cortex

Brain Res.

(1991)

K. Vass et al.

Induction of stress protein HSP70 in nerve cells after status epilepticus in the rat

Neurosci. Lett.

(1989)

G. An et al.

Expression of c-fos and c-jun family genes after focal cerebral ischemia

Ann. Neurol.

(1993)

J. Ananthan et al.

Abnormal proteins serve as eukaryotic stress signals and trigger the activation of heat shock genes

Science

(1986)

H. Benveniste et al.

Mechanism of detection of acute cerebral ischemia in rats by diffusion-weighted magnetic resonance microscopy

Stroke

(1992)

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)

E. Busch et al.

Simultaneous recording of EEG, DC potential and diffusion-weighted NMR imaging during potassium induced cortical spreading depression in rats

NMR Biomed.

(1995)

A.L. Busza et al.

Diffusion-weighted imaging studies of cerebral ischemia in gerbils. Potential relevance to energy failure

Stroke

(1992)

M. Chopp et al.

Neuronal injury and expression of 72-kDa heat-shock protein after forebrain ischemia in the rat

Acta Neuropathol. (Berlin)

(1991)

Y. Collaco-Moraes et al.

Focal ischemia causes an extensive induction of immediate early genes that are sensitive to MK-801

Stroke

(1994)

T. Curran et al.

Fos: an immediate-early transcription factor in neurons

J. Neurobiol.

(1995)

A.J. de Crespigny et al.

Perfusion and diffusion MR imaging of thromboembolic stroke

J. Magn. Reson. Imaging

(1993)

C. Decanniere et al.

Correlation of rapid changes in the average water diffusion constant and the concentrations of lactate and ATP breakdown products during global ischemia in cat brain

Magn. Reson. Med.

(1995)

T. Els et al.

Hyperglycemia delays terminal depolarization and enhances repolarization after peri-infarct spreading depression as measured by serial diffusion MR mapping

J. Cereb. Blood Flow Metab.

(1997)

P. Gass et al.

Induction of FOS and JUN proteins after focal ischemia in the rat: differential effect of the N-methyl-D-aspartate receptor antagonist MK-801

Acta Neuropathol. (Berlin)

(1992)

R. Gill et al.

The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischaemia in the rat

J. Cereb. Blood Flow Metab.

(1992)

S.A. Glantz, Primer of Biostatistics, 3rd edn., McGraw Hill, New York,...

S.A. Glantz, Primer of Bio-Statistics: The Program, 3rd edn., McGraw Hill, New York,...

Y. Hasegawa et al.

Spreading waves of a reduced diffusion coefficient of water in normal and ischemic rat brain

J. Cereb. Blood Flow Metab.

(1995)

K.A. Hossmann

Periinfarct depolarizations

Cerebrovasc. Brain Metab. Rev.

(1996)

C. Hunt et al.

Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70

Proc. Natl. Acad. Sci. U.S.A.

(1985)

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Research reportTransient MRI-detected water apparent diffusion coefficient reduction correlates with c-fos mRNA but not hsp70 mRNA induction during focal cerebral ischemia in rats

Abstract

Introduction

Section snippets

Animal model

Physiological data

30-min MCA occlusion images and maps

Discussion

Conclusions

Acknowledgements

Magn. Reson. Imaging

Neuron

J. Neurol. Sci.

Brain Res. Mol. Brain Res.

Neuroscience

Brain Res.

Prog. Neurobiol.

Neurosci. Lett.

Brain Res.

J. Neurol. Sci.

Curr. Opin. Genet. Dev.

Brain Res.

Trends Neurosci.

Cell

Exp. Neurol.

Brain Res.

Neurosci. Lett.

Expression of c-fos and c-jun family genes after focal cerebral ischemia

Ann. Neurol.

Abnormal proteins serve as eukaryotic stress signals and trigger the activation of heat shock genes

Science

Mechanism of detection of acute cerebral ischemia in rats by diffusion-weighted magnetic resonance microscopy

Stroke

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.

Simultaneous recording of EEG, DC potential and diffusion-weighted NMR imaging during potassium induced cortical spreading depression in rats

NMR Biomed.

Diffusion-weighted imaging studies of cerebral ischemia in gerbils. Potential relevance to energy failure

Stroke

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Acta Neuropathol. (Berlin)

Focal ischemia causes an extensive induction of immediate early genes that are sensitive to MK-801

Stroke

Fos: an immediate-early transcription factor in neurons

J. Neurobiol.

Perfusion and diffusion MR imaging of thromboembolic stroke

J. Magn. Reson. Imaging

Correlation of rapid changes in the average water diffusion constant and the concentrations of lactate and ATP breakdown products during global ischemia in cat brain

Magn. Reson. Med.

Hyperglycemia delays terminal depolarization and enhances repolarization after peri-infarct spreading depression as measured by serial diffusion MR mapping

J. Cereb. Blood Flow Metab.

Induction of FOS and JUN proteins after focal ischemia in the rat: differential effect of the N-methyl-D-aspartate receptor antagonist MK-801

Acta Neuropathol. (Berlin)

The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischaemia in the rat

J. Cereb. Blood Flow Metab.

Spreading waves of a reduced diffusion coefficient of water in normal and ischemic rat brain

J. Cereb. Blood Flow Metab.

Periinfarct depolarizations

Cerebrovasc. Brain Metab. Rev.

Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70

Proc. Natl. Acad. Sci. U.S.A.

Research report
Transient MRI-detected water apparent diffusion coefficient reduction correlates with c-fos mRNA but not hsp70 mRNA induction during focal cerebral ischemia in rats