(Stroke. 1999;30:2416-2422.)
© 1999 American Heart Association, Inc.
Original Contributions |
Mild Hypothermia Improves Recovery of Cortical Extracellular Potassium Ion Activity and Excitability After Middle Cerebral Artery Occlusion in the Rat
From the Department of Neurology, University of Miami School of Medicine, Miami, Fla.
Correspondence to: Thomas J. Sick, PhD, Department of Neurology, University of Miami, South Campus, Bldg B, 12500 SW 152 St, Miami, FL 33177. e-mail tsick{at}neuron.med.miami.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Background and Purpose—Mild brain hypothermia significantly alleviates damage after focal ischemia, although the mechanism of this protection remains poorly defined. In the present study, we tested the hypothesis that mild hypothermia would protect cortex from early deterioration of ion homeostasis and loss of excitability associated with reperfusion after focal ischemia.
Methods—Cortical extracellular potassium ion activity ([K+]o) and the response of [K+]o to direct cortical stimulation was measured both in the ischemic core and in the ischemic penumbra of normothermic and mildly hypothermic (31.5°C to 32°C) rats after distal middle cerebral artery occlusion (MCAO) and reperfusion.
Results—The response of [K+]o during MCAO was similar in normothermic and hypothermic animals. However, within 1 hour of reperfusion, [K+]o in the ischemic core region of normothermic animals showed incomplete recovery and was refractory to direct cortical stimulation. [K+]o in hypothermic animals returned to preischemic levels on reperfusion and continued to respond to direct cortical stimulation. Mild hypothermia prevented extensive infarction 24 hours after transient MCAO.
Conclusions—The data suggest that transient focal ischemia is accompanied by early disturbances of potassium ion homeostasis during reperfusion, which are accompanied by loss of excitability and which may contribute ultimately to cortical infarction.
Key Words: cerebral infarction • reperfusion • stroke • temperature • rats
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Mild hypothermia (2°C to 3°C below normal) significantly protects the brain from damage after ischemia. After global forebrain ischemia, mild hypothermia protects selectively vulnerable neurons from delayed damage,1 2 3 although this protection might be short-lived.4 Several investigators have shown that hypothermia after focal ischemia reduces infarction.5 6 7 8 9 In contrast, mild hyperthermia aggravates ischemic neuronal damage after global forebrain ischemia10 11 12 and increases infarction after focal ischemia.13 14 Although the importance of brain temperature in minimizing or exacerbating brain damage after ischemia is well recognized, the mechanisms underlying this sensitivity to temperature remain poorly understood.
Foremost among the processes that might explain the temperature sensitivity of brain to ischemia are energy metabolism and functions requiring high energy use, such as ion transport. Ischemia is well known to be accompanied within minutes by sudden, large shifts in the concentrations of most extracellular ion species (anoxic depolarization [AD]), which suggests ionic equilibration across cellular membranes.15 In focal ischemia, these changes are limited to regions of severely limited blood flow.16 17 18 19 However, in regions that surround the ischemic core, transient ionic disturbances occur that closely resemble cortical spreading depression (SD).20 The ionic changes associated with focal ischemia are important because they may contribute to brain infarction.21 22
Few reports exist on the effects of temperature on brain ion homeostasis after ischemia. However, a consensus seems to exist that hypothermia does not prevent AD associated with either global or focal ischemia, although studies have reported that the onset of AD may be delayed.13 23 24 Data also have been reported that indicate that mild hypothermia reduces the number of SD-like depolarizations associated with focal ischemia.13 The frequency of SD-like depolarizations has been associated with the degree of damage after focal ischemia.25 26
Although considerable interest has been generated in the ionic changes that occur during focal ischemia, little attention has been paid to disturbances associated with reperfusion. Most earlier investigations, for example, have shown that extracellular potassium ion activity ([K+]o) recovers to or near preischemic levels upon reperfusion,17 27 which suggests normalization of potassium ion homeostasis. However, we have recently shown that focal ischemia is accompanied by early secondary elevation of [K+]o, which is dependent on brain temperature but not blood flow.19
The goals of the present study were (1) to further investigate restoration of cortical potassium ion homeostasis after transient focal ischemia; (2) to investigate whether ischemia-induced alterations in cortical potassium ion homeostasis are accompanied changes in cortical excitability; and (3) to determine whether mild hypothermia protects against any ionic and excitability disturbances provoked by focal ischemia.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Animal Preparation and Distal Middle Cerebral Artery Occlusion
All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health and were approved by the animal care committee of the University of Miami. Fasted male Sprague Dawley rats (n=20; weight, 280 to 340 g) were initially anesthetized with 3% halothane in 30% oxygen/70% nitrous oxide. The animals were intubated, placed on positive-pressure ventilation with 1% halothane in 30% oxygen/70% nitrous oxide, and immobilized with 0.75 mg/kg pancuronium bromide. Polyethylene catheters were placed in the femoral arteries for monitoring blood pressure, sampling arterial blood for blood gas analysis, and supplementing pancuronium when necessary. Oxygen content of the inspired gas mixture, ventilatory rate, and stroke volume were adjusted to maintain blood gas values and pH in the normal range.
Each rat was placed in a head-restraining device, the skin overlying the skull was reflected, and 3 burr holes were made in the right side of the skull. One hole in the zygomatic bone exposed the distal middle cerebral artery (MCA) at the point at which it crossed the inferior cerebral vein. The second hole was 2 mm in diameter and was placed 6 to 7 mm lateral and 1 mm posterior to bregma (ischemic core region). The third hole was 2 mm in diameter and was placed 1 mm lateral and 1 mm anterior to lambda (penumbra). The dura overlying the cortex in each region was gently removed by microdissection. A small hook was placed under the distal MCA under microscopic control and was held in a micromanipulator. Retraction of the hook completely occluded the distal MCA. Brain temperature was monitored with a 33-gauge thermocouple inserted between the skull and the dura. Brain temperature was maintained throughout ischemia and for 1 hour of reperfusion at 35°C to 36°C (normothermia) or 31.5°C to 32°C (mild hypothermia) with a lamp connected to a temperature-regulated electrical relay.
The distal MCA was occluded for 1 hour by gentle retraction of the hook, and ischemia was confirmed by sudden elevation of [K+]o to >50 mmol/L in the core region. The sudden elevation of [K+]o indicated that cerebral blood flow was reduced to less than the ischemic threshold and thus was used to confirm that the severity of ischemia was similar in all animals. In initial experiments, elevation of [K+]o after distal MCA occlusion (MCAO) was often incomplete or transient, which indicated incomplete ischemia or reflow from collateral circulation. To ensure completeness of ischemia in all animals, blood pressure was lowered by withdrawal of arterial blood into a heparinized syringe so that [K+]o remained elevated to >50 mmol/L for the entire 1-hour period. Reperfusion was accomplished by releasing occlusion of the MCA and by returning blood to the femoral artery to raise blood pressure. A subpopulation of animals (n=5) was allowed to recover after MCAO and was reanesthetized 24 hours later for subsequent analysis of cortical [K+]o.
Measurements of [K+]o
[K+]o was measured
with double-barreled microelectrodes as described
earlier.28 The microelectrodes were inserted into the
cortex to a depth of approximately 500 µm from the surface
through burr holes positioned over the ischemic core and
ischemic penumbra (see above). All
K+-sensitive microelectrodes were calibrated at
room temperature. No effect of temperature was observed on calibrations
over a range of37°C to 27°C. Cortical excitability was determined
by applying constant current pulses directly to the cortex in the
vicinity of the [K+]o
recording electrodes. We chose this method instead of
stimulation of an afferent pathway to avoid possible complications as a
result of postischemic inhibition of synaptic transmission.
Bipolar stimulating electrodes (1-mm tip separation) were placed on
either side of the K+-sensitive microelectrode so
that electric current could be passed through the cortex in which
[K+]o measurements were
made. Increased [K+]o was
provoked by applying 2-second trains (20 Hz) of constant current pulses
(0.5-millisecond duration) directly to the cortical surface. Identical
current intensities were used before MCAO, 1 hour after reperfusion,
and again 24 hours after reperfusion.
Measurement of Cortical Infarct Area
Because [K+]o
measurements were conducted in cortex, cortical surface infarct area
rather than infarct volume was estimated. After completion of
[K+]o measurements 24
hours after brain reperfusion, rats were euthanatized and their brains
were removed and immersed in a 2% solution of
2,3,5-triphenyltetrazolium hydrochloride
(TTC) in normal saline at 37°C for 1 hour. After staining, the brains
were fixed in 10% phosphate-buffered formalin for photography and
digital analysis of infarct area. Infarction was estimated from
the cortical surface by removing the cortex from subcortical
structures, sectioning it at the frontal and occipital poles, and
laying it flat on a cover slip. This procedure was used to eliminate
cortical curvature (similar to a Mercator map projection) for
facilitation of estimates of surface infarct area. Digital images of
the cortical surface were recorded, and both the total cortical
area and the area of infarction (unstained region) were measured by
digital morphometry. Infarct area was calculated as a percentage of the
total cortical area. Estimates of infarct area were used solely to
confirm hypothermic protection, and no attempts were made to relate
point measurements of
[K+]o to regions of
infarction.
Statistical Analysis
Although measurements of
[K+]o were continuous,
for statistical purposes, values were sampled before ischemia,
at the end of 1 hour of MCAO, 1 hour after reperfusion, and again at 24
hours after reperfusion. Values are expressed as the mean±SE of the
mean and were compared by ANOVA for repeated measures. The method of
orthogonal contrasts was used for post hoc comparisons of individual
means. Student's t test was used when only a single
comparison among groups was warranted (eg, comparison of latency to
depolarization during MCAO).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Blood Chemistry
Before the onset of ischemia (and brain hypothermia), arterial PO2, PCO2, and pH averaged 111.6±15.3 mm Hg, 37.4±4.5 mm Hg, and 7.46±0.05, respectively, in normothermic animals. In animals designated for mild hypothermia, arterial PO2, PCO2, and pH averaged 126.5±13.7 mm Hg, 39.2±4.4 mm Hg, and 7.44±0.05, respectively. More importantly for the present study, arterial PO2, PCO2, and pH averaged 115.2±15.4 mm Hg, 38.5±4.1 mm Hg, and 7.39±0.06, respectively, in normothermic animals during reperfusion. In hypothermic animals, arterial PO2, PCO2, and pH averaged 129.1±19.5 mm Hg, 37.1±2.7 mm Hg, and 7.42±0.04, respectively, during reperfusion after focal ischemia. No statistical differences in blood gases and pH were observed between normothermic and hypothermic animals during reperfusion after focal ischemia.
Effect of MCAO on [K+]o in Core and
Penumbra of Normothermic and Hypothermic Animals
In both normothermic and hypothermic animals, distal
MCAO resulted in elevation of resting (unstimulated)
[K+]o in core and
penumbral regions of cortex. Examples of these changes in cortical
[K+]o are shown in Figure 1
. Values recorded before
ischemia, 1 hour after onset of MCAO, 1 hour after reperfusion,
and 24 hours after reperfusion are shown in Figures 2A (core) and B (penumbra). During
MCAO, [K+]o in the core
of both normothermic and hypothermic animals was
significantly elevated from preischemic levels
(F=78.8; P<0.0001), and no significant
differences were observed between the 2 groups. In
normothermic animals, core
[K+]o during MCAO
averaged 60.3± 3.48 mmol/L (mean±SD), whereas in hypothermic
animals, it averaged 50.6±4.9 mmol/L. Moreover, mild hypothermia
did not prevent or significantly delay the onset of
[K+]o elevation in
cortical ischemic core. In normothermic animals,
the latency to [K+]o
elevation after MCAO averaged 48.6±7.2 seconds, whereas in hypothermic
animals, the latency was 57.6±7.3 seconds (t=0.83;
P=0.2).
|
|
One hour after reperfusion, baseline [K+]o recovered to 4.5±1.4 and 3.1±0.8 mmol/L in normothermic and hypothermic animals, respectively. Twenty-four hours after reperfusion, baseline [K+]o was 5.7±2.2 mmol/L in normothermic animals and 3.05±0.6 mmol/L in hypothermic animals. During reperfusion, [K+]o in the core of normothermic animals remained significantly elevated above preischemic levels both at 1 hour (F=6.8, P<0.05) and 24 hours (F=9.3, P<0.01). In hypothermic animals, no significant elevation of [K+]o was found following reperfusion after MCAO either at 1 or 24 hours.
In penumbra, resting
[K+]o (excluding SD-like
events) was not significantly elevated above preischemic
levels during MCAO or at any time after reperfusion. However, in
penumbra, transient depolarizing waves were observed during which
[K+]o was elevated to
near 50 mmol/L (see Figure 1
). These transient events
resembled cortical SD associated with MCAO, which has been described by
others.20 29 30 The frequency and duration of the SD-like
events was highly variable and ranged in frequency from 1 to 5 per
1-hour ischemic episode and in duration from 30 seconds to
approximately 10 minutes. SD-like events were not observed following
reperfusion after MCAO. No significant difference was found in the
frequency of SD-like events, which in penumbra averaged 2.17±1.0 in
normothermic animals and 2.89±1.2 in hypothermic animals.
No apparent effect of hypothermia was found on the duration of SD-like
events, although great variability in the waveform of these events
(duration range, 1 to 5 minutes) precluded meaningful
analysis.
Effect of Mild Hypothermia on [K+]o After
Direct Cortical Stimulation
Before MCAO, direct cortical stimulation (DCS) resulted in
transient elevation of
[K+]o both in
regions destined to become ischemic core and in regions
destined to become penumbra (Figure 3).
In normothermic animals, DCS failed to elevate
[K+]o during MCAO in
ischemic core as expected (data not shown) but also failed to
elevate [K+]o 1 hour
after reperfusion, when baseline
[K+]o had returned to
near preischemic levels (Figure 3A, top trace).
Elevation of [K+]o after
DCS in penumbra was possible but was attenuated (Figure 3A, bottom trace). Mild hypothermia protected cerebral cortex against loss
of excitability (indicated by response of
[K+]o to DCS) in both
core (Figure 3B, top trace) and penumbra (Figure 3B, bottom trace) 1 hour following reperfusion after MCAO.
|
The average changes in
[K+]o after DCS
(
[K+]o) recorded
in normothermic and hypothermic animals following
reperfusion after MCAO are shown in Figure 4. Mild hypothermia significantly
protected against loss of excitability after MCAO (F=9.83,
P=0.004). In the ischemic core region of
normothermic animals, MCAO resulted in attenuation of
[K+]o to 16.2±6.3%
of preischemic values 1 hour after reperfusion. In
hypothermic animals,
[K+]o in the core
region recovered to 57.2±15.8% of preischemic values.
|
Mild hypothermia also tended to improve recovery of
[K+]o in penumbra,
although the degree of improvement was not as dramatic because of the
lack of initial MCAO-induced impairment compared with the core region.
In penumbra, [K+]o in
normothermic animals recovered to 39.1±13.7% of
preischemic values 1 hour after reperfusion after MCAO. In
hypothermic animals,
[K+]o in penumbra
improved to 70.1±11.3% of preischemic values.
The response of cortical [K+]o to DCS 24 hours following reperfusion after MCAO also was tested in a limited number of animals. As expected, no response of [K+]o to DCS of the core region was seen in 5 of 5 normothermic animals. In hypothermic animals, only 2 of 5 animals failed to respond to DCS in the core 24 hours after MCAO. In the penumbra, 2 of 4 normothermic animals responded positively to DCS, whereas 6 of 6 hypothermic animals responded positively. The high variability among animals 24 hours after MCAO precluded meaningful statistical analysis, especially in the ischemic core region. However, some protection due to hypothermia still did appear to be evident at this time.
Effect of Mild Hypothermia on Cortical Infarction After
MCAO
One hour of distal MCAO in normothermic animals
consistently resulted in cortical infarction (measured by TTC
staining) 24 hours after reperfusion. Mild hypothermia profoundly
protected against cortical infarction. Average estimates of surface
infarction area in normothermic and hypothermic animals are
shown Figure 5. The average area of
infarction in normothermic animals was 16.6±3.9% of the
total cortical surface, whereas in hypothermic animals, the average
infarction area was reduced to 1.4±2.0% of the cortical surface.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
In the present study, we compared the recovery of cortical potassium ion homeostasis after 1 hour of transient distal MCAO in normothermic and mildly hypothermic animals. In addition to recovery of resting [K+]o, we evaluated release of K+ in response to DCS as an indication of cortical excitability. In normothermic animals, reperfusion after 1 hour of transient MCAO resulted in incomplete restoration of [K+]o, failure of [K+]o to increase with DCS, and widespread infarction 24 hours later. Mild hypothermia prevented the changes in K+ homeostasis and the ensuing infarction. The data indicate that ionic disturbances are evident very early following reperfusion after focal ischemia and that these early changes are temperature dependent.
The protective effect of mild hypothermia against cerebral infarction after focal ischemia is well documented.6 8 9 31 32 33 34 Early investigations sought to determine whether intraischemic hypothermic protection resulted from preservation of energy metabolism. Although the rate of decline of high-energy phosphates such as ATP and phosphocreatine was slowed by mild hypothermia,35 ischemic levels of these compounds nonetheless were observed within minutes. The suggestion that mild brain hypothermia does not provide protection by significantly slowing rates of ATP utilization was indirectly supported by measurements of ionic changes such as [K+]o. The sudden elevation of [K+]o seen during ischemia has been related to the decline in ATP levels associated with ischemia. Although hypothermia has been reported to delay the onset of [K+]o elevation after ischemia,23 24 36 the delay is only a few minutes and not likely to contribute significantly to the damage that ensues during focal ischemia, which might persist for >1 hour. Results from the present study further support the notion that hypothermic protection does not result from delaying the onset of energy failure and loss of ion homeostasis. First, the onset of sudden depolarization was not significantly delayed by mild hypothermia. Second, in the present study, the duration of focal ischemia was determined from the onset of depolarization so that normothermic and hypothermic animals remained in the depolarized state for exactly 1 hour. Thus, data from the present study indicate that mild hypothermia during brain ischemia does not provide protection by reducing energy use and subsequently by delaying neuronal depolarization.
A related issue that concerns mild hypothermia and infarct size after focal cerebral ischemia is the role of transient SD-like depolarizations. SD-like events have been shown to occur in penumbra and nonischemic regions of cerebral cortex after focal cerebral ischemia.20 Moreover, the frequency of these events has been related to infarct volume.25 26 37 38 We observed no significant decrease in the frequency of SD-like elevations of [K+]o in penumbra of hypothermic animals compared with normothermic animals. This appears to be in contrast with the observations of Chen et al,13 who reported that hypothermia decreased the number of DC deflections recorded after MCAO by intraluminal suture insertion. However, their study did not make clear whether the DC deflections were recorded in the ischemic core or in the penumbra. If the recordings were in the ischemic core, then repeated DC deflections might have indicated incomplete ischemia rather than SD-like events, because the latter should not be observed in completely depolarized tissue (ie, ischemic core). In the present study, the ischemic core remained depolarized throughout 1 hour of ischemia by lowering arterial blood pressure. In the absence of hypotension, we often observed incomplete or spontaneously reversible elevation of [K+]o during MCAO. However, on the basis of our data, we conclude that hypothermia did not reduce infarction by limiting the number of SD-like peri-infarct depolarizations.
Our data are more consistent with the hypothesis that hypothermia protects against infarction by preventing secondary loss of ion homeostasis associated with reperfusion.19 Loss of ion homeostasis was indicated both by elevation of resting [K+]o and by the failure of DCS to elicit elevation of [K+]o. Gido et al17 also reported a secondary rise in [K+]o following reperfusion after MCAO, but in their study, the delayed elevation occurred 6 hours after the onset of reperfusion. Secondary elevation of [K+]o might reflect reperfusion-induced deterioration of brain energy state39 related to secondary failure of mitochondrial function.40 41
The failure of [K+]o to elevate after DCS likely did not result solely from elevation of resting [K+]o, which was only a few millimoles per liter greater than normal levels. Failure of [K+]o to respond to DCS suggests incomplete neuronal repolarization to the point of blocking action potential discharges. However, the fact that [K+]o recovers during reperfusion indicates that some restoration of transmembrane potential has occurred. Other investigators have shown that total brain potassium ion levels decrease after focal brain ischemia,18 42 which indicates a decrease in [K+]i, which would further magnify neuronal depolarization by reducing the transmembrane potassium ion gradient. However, it is also possible that ischemia or reperfusion may directly alter properties of ion transport molecules, voltage-dependent ion channels in neurons, or release of excitatory neurotransmitters such as glutamate. For example, oxyradical formation, which increases after brain ischemia in a temperature-dependent manner,43 44 has been reported to inhibit neuronal Na+,K+-ATPase.45 46
In conclusion, we have shown in the present study changes in cortical potassium ion homeostasis and excitability that occur as early as 1 hour following reperfusion after transient focal cerebral ischemia. These ionic disturbances were ameliorated by mild brain hypothermia, as was subsequent cortical infarction measured 24 hours later. An important question not resolved by the present study is whether early changes in ion homeostasis following reperfusion after focal ischemia contribute to or cause eventual tissue infarction. It is also be important to determine the window of protection provided by mild hypothermia for preservation of ion homeostasis and excitability.
|
Acknowledgments |
|---|
This research was supported in part by PHS grants NS-14325, NS-32167 (T.J.S.), and NS-34773 (M.A.P.).
Received July 6, 1999; accepted August 27, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
1. Busto R, Dietrich WD, Globus MY, Ginsberg MD. The importance of brain temperature in cerebral ischemic injury. Stroke. 1989;20:1113–1114.
2. Busto R, Dietrich WD, Globus MY, Ginsberg MD. Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett. 1989;101:299–304.[Medline] [Order article via Infotrieve]
3. Minamisawa H, Smith ML, Siesjo BK. The effect of mild hyperthermia and hypothermia on brain damage following 5, 10, and 15 minutes of forebrain ischemia. Ann Neurol. 1990;28:26–33.[Medline] [Order article via Infotrieve]
4. Dietrich WD, Busto R, Alonso O, Globus MY, Ginsberg MD. Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab. 1993;13:541–549.[Medline] [Order article via Infotrieve]
5. Baker CJ, Onesti ST, Solomon RA. Reduction by delayed hypothermia of cerebral infarction following middle cerebral artery occlusion in the rat: a time-course study. J Neurosurg. 1992;77:438–444.[Medline] [Order article via Infotrieve]
6. Goto Y, Kassell NF, Hiramatsu K, Soleau SW, Lee KS. Effects of intraischemic hypothermia on cerebral damage in a model of reversible focal ischemia [published discussion appears in Neurosurgery.. 1993;32:984–985]. Neurosurgery. 1993; 32:980–984.
7. Karibe H, Chen J, Zarow GJ, Graham SH, Weinstein PR. Delayed induction of mild hypothermia to reduce infarct volume after temporary middle cerebral artery occlusion in rats. J Neurosurg. 1994;80:112–119.[Medline] [Order article via Infotrieve]
8. Morikawa E, Ginsberg MD, Dietrich WD, Duncan RC, Kraydieh S, Globus MY, Busto R. The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1992;12:380–389.[Medline] [Order article via Infotrieve]
9.
Moyer DJ, Welsh FA, Zager EL. Spontaneous cerebral
hypothermia diminishes focal infarction in rat brain.
Stroke. 1992;23:1812–1816.
10. Busto R, Globus MY, Neary JT, Ginsberg MD. Regional alterations of protein kinase C activity following transient cerebral ischemia: effects of intraischemic brain temperature modulation. J Neurochem. 1994;63:1095–1103.[Medline] [Order article via Infotrieve]
11.
Dietrich WD, Busto R, Valdes I, Loor Y. Effects of
normothermic versus mild hyperthermic forebrain
ischemia in rats. Stroke. 1990;21:1318–1325.
12. Kuroiwa T, Bonnekoh P, Hossmann KA. Prevention of postischemic hyperthermia prevents ischemic injury of CA1 neurons in gerbils. J Cereb Blood Flow Metab. 1990;10:550–556.[Medline] [Order article via Infotrieve]
13. Chen Q, Chopp M, Bodzin G, Chen H. Temperature modulation of cerebral depolarization during focal cerebral ischemia in rats: correlation with ischemic injury. J Cereb Blood Flow Metab. 1993;13:389–394.[Medline] [Order article via Infotrieve]
14. Zhao Q, Pahlmark K, Smith ML, Siesjo BK. Delayed treatment with the spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats. Acta Physiol Scand. 1994;152:349–350.[Medline] [Order article via Infotrieve]
15. Hansen AJ, Nedergaard M. Brain ion homeostasis in cerebral ischemia. Neurochem Pathol. 1988;9:195–209.[Medline] [Order article via Infotrieve]
16. Branston NM, Strong AJ, Symon L. Extracellular potassium activity, evoked potential and tissue blood flow: relationships during progressive ischaemia in baboon cerebral cortex. J Neurol Sci. 1977;32:305–321.[Medline] [Order article via Infotrieve]
17.
Gido G, Kristian T, Siesjo BK. Extracellular potassium
in a neocortical core area after transient focal ischemia.
Stroke. 1997;28:206–210.
18. Schielke GP, Moises HC, Betz AL. Blood to brain sodium transport and interstitial fluid potassium concentration during early focal ischemia in the rat. J Cereb Blood Flow Metab. 1991;11:466–471.[Medline] [Order article via Infotrieve]
19. Sick TJ, Tang R, Perez-Pinzon MA. Cerebral blood flow does not mediate the effect of brain temperature on recovery of extracellular potassium ion activity after transient focal ischemia in the rat. Brain Res. 1999;821:400–406.[Medline] [Order article via Infotrieve]
20. Nedergaard M, Hansen AJ. Characterization of cortical depolarizations evoked in focal cerebral ischemia. J Cereb Blood Flow Metab. 1993;13:568–574.[Medline] [Order article via Infotrieve]
21. Betz AL, Ennis SR, Schielke GP. Blood-brain barrier sodium transport limits development of brain edema during partial ischemia in gerbils [published erratum appears in Stroke. 1990;21:1095]. Stroke. 1989;20:1253–1259.
22.
Young W, Rappaport ZH, Chalif DJ, Flamm ES. Regional
brain sodium, potassium, and water changes in the rat middle cerebral
artery occlusion model of ischemia. Stroke. 1987;18:751–759.
23. Astrup J, Skovsted P, Gjerris F, Sorensen HR. Increase in extracellular potassium in the brain during circulatory arrest: effects of hypothermia, lidocaine, and thiopental. Anesthesiology. 1981;55:256–262.[Medline] [Order article via Infotrieve]
24. Lantos J, Temes G, Torok B. Changes during ischaemia in extracellular potassium ion concentration of the brain under nitrous oxide or hexobarbital-sodium anaesthesia and moderate hypothermia. Acta Physiol Hung. 1986;67:141–153.[Medline] [Order article via Infotrieve]
25. Busch E, Gyngell ML, Eis M, Hoehn-Berlage M, Hossmann KA. 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;16:1090–1099.[Medline] [Order article via Infotrieve]
26. Nedergaard M, Astrup J. Infarct rim: effect of hyperglycemia on direct current potential and [14C]2-deoxyglucose phosphorylation. J Cereb Blood Flow Metab. 1986;6:607–615.[Medline] [Order article via Infotrieve]
27. Branston NM, Symon L, Strong AJ. Reversibility of ischaemically induced changes in extracellular potassium in primate cortex. J Neurol Sci. 1978;37:37–49.[Medline] [Order article via Infotrieve]
28. Raffin CN, Sick TJ, Rosenthal M. Inhibition of glycolysis alters potassium ion transport and mitochondrial redox activity in rat brain. J Cereb Blood Flow Metab. 1988;8:857–865.[Medline] [Order article via Infotrieve]
29. Dietrich WD, Feng ZC, Leistra H, Watson BD, Rosenthal M. Photothrombotic infarction triggers multiple episodes of cortical spreading depression in distant brain regions. J Cereb Blood Flow Metab. 1994;14:20–28.[Medline] [Order article via Infotrieve]
30. Back T, Ginsberg MD, Dietrich WD, Watson BD. Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occlusion: effect on infarct morphology. J Cereb Blood Flow Metab. 1996;16:202–213.[Medline] [Order article via Infotrieve]
31. Michenfelder JD. Cerebral preservation for intraoperative focal ischemia. Clin Neurosurg. 1985;32:105–113.[Medline] [Order article via Infotrieve]
32. Jiang Q, Chopp M, Zhang ZG, Helpern JA, Ordidge RJ, Ewing J, Jiang P, Marchese BA. The effect of hypothermia on transient focal ischemia in rat brain evaluated by diffusion- and perfusion-weighted NMR imaging. J Cereb Blood Flow Metab. 1994;14:732–741.[Medline] [Order article via Infotrieve]
33. Kozlowski P, Buchan AM, Tuor UI, Xue D, Huang ZG, Chaundy KE, Saunders JK. Effect of temperature in focal ischemia of rat brain studied by 31P and 1H spectroscopic imaging. Magn Res Med. 1997;37:346–354.[Medline] [Order article via Infotrieve]
34. Barone FC, Feuerstein GZ, White RF. Brain cooling during transient focal ischemia provides complete neuroprotection. Neurosci Biobehav Rev. 1997;21:31–44. Review.[Medline] [Order article via Infotrieve]
35. Welsh FA, Sims RE, Harris VA. Mild hypothermia prevents ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab. 1990;10:557–563.[Medline] [Order article via Infotrieve]
36. Astrup J, Rehncrona S, Siesjo BK. The increase in extracellular potassium concentration in the ischemic brain in relation to the preischemic functional activity and cerebral metabolic rate. Brain Res. 1980;199:161–174.[Medline] [Order article via Infotrieve]
37. Mies G, Iijima T, Hossmann KA. Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Neuroreport. 1993;4:709–711.[Medline] [Order article via Infotrieve]
38. Takano K, Latour LL, Formato JE, Carano R, Helmer KG, Hasegawa Y, Sotak CH, Fisher M. The role of spreading depression in focal ischemia evaluated by diffusion mapping. Ann Neurol. 1996;39:308–318.[Medline] [Order article via Infotrieve]
39. Folbergrova J, Zhao Q, Katsura K, Siesjo BK. N-tert-butyl-alpha-phenylnitrone improves recovery of brain energy state in rats following transient focal ischemia. ProcNatl Acad SciU S A. 1995;92:5057–5061.
40. Kuroda S, Katsura KI, Tsuchidate R, Siesjo BK. Secondary bioenergetic failure after transient focal ischaemia is due to mitochondrial injury. Acta Physiol Scand. 1996;156:149–150.[Medline] [Order article via Infotrieve]
41. Kuroda S, Katsura K, Hillered L, Bates TE, Siesjo BK. Delayed treatment with alpha-phenyl-N-tert-butyl nitrone (PBN) attenuates secondary mitochondrial dysfunction after transient focal cerebral ischemia in the rat. Neurobiol Dis. 1996;3:149–157.[Medline] [Order article via Infotrieve]
42. Betz AL, Keep RF, Beer ME, Ren XD. Blood-brain barrier permeability and brain concentration of sodium, potassium, and chloride during focal ischemia. J Cereb Blood Flow Metab. 1994;14:29–37.[Medline] [Order article via Infotrieve]
43. Karibe H, Chen SF, Zarow GJ, Gafni J, Graham SH, Chan PH, Weinstein PR. Mild intraischemic hypothermia suppresses consumption of endogenous antioxidants after temporary focal ischemia in rats. Brain Res. 1994;649:12–18.[Medline] [Order article via Infotrieve]
44. Globus MYT, Busto R, Lin B, Schnippering H, Ginsberg M. Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation. J Neurochem. 1995;65:1250–1256.[Medline] [Order article via Infotrieve]
45. Mark RJ, Hensley K, Butterfield DA, Mattson MP. Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J Neurosci. 1995;15:6239–6249.[Abstract]
46. Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP. A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J Neurochem. 1997;68:255–264.[Medline] [Order article via Infotrieve]
Editorial Comment
Department of Internal Medicine, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
Mild brain hypothermia is known to be neuroprotective and to limit the extent of brain injury in experimental models of focal cerebral ischemia.1 Conversely, mild hyperthermia increases injury in the same experimental models. The mechanisms that account for the protective effect of hypothermia during ischemia are not well defined, however.
Ischemia is associated with many molecular, biochemical, and cellular changes that may contribute to brain injury. These changes include alterations to the normally tight regulation of ion homeostasis that is present in brain. For example, ischemia produces large changes in extracellular levels of potassium ion. The present study examined the hypothesis that hypothermia (to about 32°C) would protect the brain from deterioration of ion homeostasis, loss of excitability, and injury after focal ischemia with reperfusion. The results of the study suggest that after transient focal ischemia, early changes in potassium ion homeostasis occur with loss of neuronal excitability and that these changes are attenuated by hypothermia.
Thus, this study provides additional insight into effects of hypothermia during cerebral ischemia and indicates that the loss of ion homeostasis following reperfusion after ischemia is temperature dependent. The precise mechanisms that mediate the effect are unclear and not defined by these experiments. Possible mechanisms by which hypothermia might affect ionic changes and brain injury after ischemia include alterations in release of neurotransmitters, reduced production or increased degradation of reactive oxygen species, or changes in function or expression of ion channels and ion transport mechanisms.
Received July 6, 1999; accepted August 27, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
|---|
1. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke.. 1998;29:529–534.
This article has been cited by other articles:
 |
|
 |
|
  S. Sinha and E.A. Warburton The evolution of stroke units--towards a more intensive approach? QJM, September 1, 2000; 93(9): 633 - 638. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||