(Stroke. 1995;26:878-884.)
© 1995 American Heart Association, Inc.
Articles |
In Vivo Studies of Extracellular Metabolites in the Striatum After Distal Middle Cerebral Artery Occlusion in Stroke-Prone Spontaneously Hypertensive Rats
From the Department of Neurosurgery, National Defense Medical College, Tokorozawa, Japan.
Correspondence to Toshiki Shirotani, MD, Department of Neurosurgery, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama 359, Japan.
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Background and Purpose We demonstrated in a previous study that 45Ca accumulation in the lateral part of the striatum was detected 3 days after distal middle cerebral artery (MCA) occlusion using a 45Ca autoradiographic technique in stroke-prone spontaneously hypertensive rats. However, the mechanism of delayed neuronal damage that occurred in the lateral part of the striatum is unknown. We examined changes in amino acids and monoamines in the striatums of rat brains after MCA occlusion in stroke-prone spontaneously hypertensive rats using an in vivo brain microdialysis technique.
Methods Microdialysis probes were inserted into the lateral or medial part of the striatum 24 hours before the experiment. The dialysis probe was perfused continuously at 2 µL/min with Ringer's solution, and the dialysate samples were collected every 20 minutes. After a 3-hour period for baseline stabilization, the right MCA was occluded. The dialysate count of monoamines and amino acids was determined by high-performance liquid chromatography.
Results After MCA occlusion, a threefold transient increase in glutamate was observed in the lateral part of the striatum. The level returned to its baseline value 60 minutes after MCA occlusion. Dopamine in the lateral part increased twofold to its peak value. This release persisted for 2 hours after MCA occlusion. There were no significant changes in these components in the extracellular fluid of the medial part of the striatum.
Conclusions Our study demonstrated that changes of neurotransmitters in the lateral part of the striatum after MCA occlusion differed from those in the medial part. These results suggest that excessive release of glutamate and dopamine is related to delayed neuronal damage that occurs in the lateral part of the striatum in this model.
Key Words: dopamine • glutamates • middle cerebral artery occlusion • rats
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Introduction |
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The striatum is highly vulnerable to ischemia. It is also richly innervated by both the corticostriatal glutamatergic pathway and nigrostriatal dopaminergic projections, which have been shown to interact with each other.1 Excitatory amino acids, such as glutamate (Glu), may contribute to ischemic cell death by causing an intracellular overload of Ca2+.2 It has been suggested that dopamine contributes to ischemic cell death by producing oxygen radicals3 or by potentiating the excitotoxic effects of Glu.4
The striatum represents the "ischemic core" and has minimal postocclusion blood flow because this area is supplied exclusively by the lenticulostriate end arteries.5 In contrast, the cortex may represent an "ischemic penumbra" where blood flow persists via a collateral supply. Park et al6 have shown that neuroprotection of MK-801 is seen in the cortex but not in the striatum after middle cerebral artery (MCA) occlusion in rats. The MCA occlusion above the rhinal fissure in stroke-prone spontaneously hypertensive rats results in infarction of a specific region of cerebral cortex.7 8 The infarct produced by this procedure does not extend to the basal ganglia. In a previous report, Shirotani et al,9 using a 45Ca autoradiographic technique, demonstrated that delayed 45Ca accumulation in the corpus callosum, the ipsilateral pyramidal tract, the ventral posterior nucleus of the thalamus, and the lateral part of the striatum was detected in the same model. Additionally, MK-801 significantly reduced neuronal damage in the striatum in this model.9 We speculate that the damage in the striatum is related to Glu. The aim of this study was to use intracerebral microdialysis to clarify changes in striatal neurotransmitters not affected by ischemia with the use of the same MCA occlusion model. Microdialysis probes were inserted in the lateral or medial parts of the striatum to allow a comparison between each part.
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Materials and Methods |
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Animal Preparation
Thirty male, stroke-prone spontaneously hypertensive rats (age, 11 to 14 weeks; weight, 250 to 300 g) were anesthetized with 50 mg/kg IP pentobarbital and prepared for in vivo microdialysis. A guide cannula (OD, 0.9 mm; model G-8, Eicom) was implanted in either the medial (n=15) or lateral (n=15) part of the right striatum for subsequent insertion of a dialysis probe. The cannula coordinates were 0.5 mm anterior, 3 mm lateral to the bregma, and 3.5 mm ventral from the brain's surface in the medial side group and 0.5 mm anterior, 4.5 mm lateral to the bregma, and 2.8 mm ventral from the brain's surface in the lateral side group. The cannula was fixed firmly to the skull with anchor screws and dental cement. A dummy probe (model D-8, Eicom) was placed inside the guide cannula. The animals were allowed to move freely within their cages. The dummy probe was removed from the guide cannula after 7 to 10 days, and a dialysis probe (OD, 0.22 mm; membrane length, 3 mm; molecular weight cutoff, 50 000; model BDP-I-8-03, Eicom) was inserted. After 24 hours, the animals were anesthetized by the inhalation of 4% halothane. The dialysis probe was perfused continuously at 2 µL/min with Ringer's solution (148 mmol/L NaCl, 2.2 mmol/L CaCl2, 4.0 mmol/L KCl). After intubation the animals were ventilated artificially with a mixture of 70% N2, 30% O2, and halothane (1.5% during surgical preparation; 0.5% to 1.0% during brain microdialysis). Body temperature was maintained between 37°C and 37.5°C with a heating lamp controlled by a rectal thermometer. A femoral artery was cannulated for electromanometer blood pressure recordings. Acid-base parameters of arterial blood samples were also measured.
Microdialysis and Ischemia
The dialysate samples were collected every 20 minutes. After a
3-hour period for baseline stabilization, the right MCA was occluded.
The operative procedures have been described in detail
elsewhere.7 8 9 10 Under an operating microscope, the right
MCA was exposed through a 2- to 3-mm burr-hole craniectomy. The MCA was
occluded with a microbipolar coagulation and divided. The occlusion was
distal to the striate branches of the MCA and 0.7 to 1 mm dorsal to the
rhinal fissure. After 2 hours of MCA occlusion, the rats were
decapitated, and their brains were placed in 4% formalin for later
evaluation of probe placement by gross dissection. One animal from the
lateral group was excluded from the study because the probe was located
outside the striatum. Monoamines and their metabolites were analyzed in
seven rats from each group. Amino acids were analyzed in the remaining
rats (Table 1
).
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Assay for Monoamines and Their Metabolites
The dialysate contents of dopamine, dihydroxyphenilacetic acid
(DOPAC), and homovanillic acid (HVA) were determined by
high-performance liquid chromatography (HPLC) with an electrochemical
detector (model ECD-100, Eicom). The column used was Eicompak MA-5ODS
(4.6 mm ID 150 mm; Eicom). The electrochemical detector was set at +750
mV versus a Ag/AgCl reference electrode. Eighty-five percent of the
mobile phase consisted of a mixture of 0.1 mol/L of citric acid
adjusted to a pH of 3.9 with sodium acetate. The remaining 15% of the
mobile phase was methanol, which was pumped at a flow rate of 1.0
mL/min. The detection limit of the assay for dopamine and its
metabolites was 0.1 pmol/L. This method also detected the serotonin
metabolite 5-hydroxyindoleacetic acid (5-HIAA).
Assay for Amino Acid
The dialysate contents of Glu, taurine (Tau), alanine (Ala),
glutamine (Gln), and 
-aminobutyric acid (GABA) were analyzed by HPLC
with electrochemical detection and precolumn derivatization. Thirty
microliters of each sample was derivatized automatically with 10 µL
of o-phthaldialdehyde (OPA) solution (10.8 mg OPA in 20 mL
of sodium borate 0.1 mol/L with 8 mL mercaptoethanol, pH 9.5) for 2
minutes in an auto-sampling injector (model 231-401, Gilson). Ten
microliters of the derivatives was injected onto an Eicompak MA-5ODS
column. The mobile phase was a 0.1 mol/L
NaH2PO4 buffer, pH 6.0, with 30% methanol,
which was pumped at a flow rate of 1.0 mL/min. The electrochemical
detector was set at +700 mV versus a Ag/AgCl reference electrode. The
limit of accurate detection for amino acids was 10 pmol/L.
Recovery Rate of Monoamines and Amino Acids
We attempted to determine the recovery of amino acids and
monoamines through the dialysis membrane before implanting a dialysis
probe in the striatum for the in vivo determination of striatal
metabolite release. Eight dialysis probes were placed in Ringer's
solution containing standard concentrations of amino acids (n=4) and
monoamines (n=4). These probes were perfused with Ringer's solution at
2 µL/min at room temperature.
Histological Examination
The other nine male, stroke-prone spontaneously
hypertensive rats were used for histological examination. The right MCA
was occluded by the same procedure. Animals were subsequently
transferred to an observation cage and permitted free access to food
and water. Twenty-four hours (n=3), 7 days (n=3), or 1 month (n=3)
after MCA occlusion, rats were deeply anesthetized with 50 mg/kg IP
pentobarbital, and transcardiac perfusion was performed with 50 mL of
saline followed by 500 mL of 4% buffered formalin solution at a
pressure of 130 cm H2O. The brains were dissected out and
kept in the same fixative for several days. The brains were carefully
cut in symmetrical coronal planes at 5 mm from the frontal pole.
Coronal sections 6 µm thick were stained with hematoxylin-eosin.
Statistical Analysis
The metabolite concentrations and physiological variables are
presented as mean±SD. The significance was tested by ANOVA,
followed by Dunnett's test or Student's t test.
Differences were considered statistically significant at
P<.05.
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Histopathologic Findings
Twenty-four hours after MCA occlusion, the infarct area was limited to the ipsilateral cerebral cortex and did not extend to the striatum (Figs 1
and 2). Numerous
pyknotic cells appeared in the dorsolateral striatum after 7 days (Fig 2). One month after MCA occlusion, marked atrophy was observed in the
ipsilateral striatum (Fig 1). Fig 2 showed neuronal loss in the lateral
part of the striatum.
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Physiological Variables
Table 1
shows the mean arterial blood pressure,
body weight, body temperature, and arterial acid-base parameters
measured just before MCA occlusion. All animals were normothermic and
hypertensive. Their arterial PO2 values were
greater than 100 mm Hg, and their arterial
PCO2 values ranged from 30 to 40 mm Hg. No
significant differences were found between groups.
Recovery Rate of Monoamines and Amino Acids
Recovery rates were 11.3±3.2% for the monoamines and 12.4±3.7%
for the amino acids. The reported metabolite values were not corrected
for recovery.
Basal Levels of Striatal Metabolites
Stable basal concentrations of extracellular amino acids and
monoamines were detected in three consecutive samples collected before
ischemia in all experimental groups. The concentrations of dialysate
metabolites collected during the control period are listed in Table 2. Baseline values were similar in each group, except
for DOPAC and dopamine.
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Changes of Striatal Amino Acids After MCA Occlusion
Changes in the concentrations of extracellular metabolites in the
striatum are shown as times basal level. The time course of the change
in Glu concentrations is illustrated in Fig 3. After MCA
occlusion, a threefold transient increase in Glu was observed in the
lateral part of the striatum. The level returned to its baseline values
60 minutes after MCA occlusion. This increase of Glu was not observed
in the medial part of the striatum. Changes in the extracellular fluid
(ECF) concentrations of Tau and GABA also are expressed as times
basal level (Fig 4). After MCA occlusion, gradual
increases in Tau and GABA were observed only in the lateral part of the
striatum. There were no significant increases in Ala and Gln.
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) or lateral (
) part of the striatum in seven rats
subjected to middle cerebral artery occlusion expressed as times basal
level. Values represent mean and SD. Glu was elevated
significantly at 20 to 40 minutes after middle cerebral artery
occlusion but then rapidly decreased to baseline. *P<.05,
**P<.01 vs preischemic values (Dunnett's test).
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Changes of Striatal Monoamines After MCA Occlusion
Fig 5 illustrates the changes in the ECF
concentrations of dopamine. In general, no significant changes in
monoamines or their metabolites occurred after MCA occlusion. The only
exception to this was the change in dopamine in the lateral part, which
increased twofold to its peak value. This release persisted for 2 hours
after MCA occlusion.
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Advantages of Subchronic Study After Microdialysis Probe Implantation
Intracerebral microdialysis is a suitable method for studying dynamic chemical changes in the ECF.11 However, microdialysis probes cause a certain degree of damage to brain tissue. Westerink and De Vries12 studied the dopamine output in acutely and subchronically (24-hour) implanted rats. Several hours after cannula implantation, the dopamine release was only partly dependent on the neuronal activity. Investigators should be aware of non–voltage-dependent neurotransmitter release from denervated nerve terminals in acute experiments. Benveniste et al13 showed increased glucose metabolism and decreased cerebral blood flow (CBF) after insertion of a microdialysis tube, and this situation was normalized after 24 hours. They also demonstrated minimal tissue changes within 1 to 2 days after the implantation of a microdialysis tube and concluded that the optimal time for commencing microdialysis after the implant appears to be 24 to 48 hours.14 Previous reports concerning striatal metabolites released after ischemic insults have stated that dialysate samples were collected and analyzed several hours after microdialysis probe insertion.15 16 17 18 Our experiments were performed 24 hours after probe implantation. It takes more than 3 days for pathological changes such as gliosis caused by long-term implantation of the probe.14 We think that striatal metabolites in our study were measured in a more physiological state than in previous reports.
Neurotransmitter Changes After MCA Occlusion
Our results suggest that focal cortical ischemia is associated
with different neurotransmitter changes in the medial and lateral parts
of the striatum. Significant increases in the extracellular
concentrations of Glu, Tau, GABA, and dopamine were observed only in
the lateral part of the striatum, where infarct area did not extend
until 24 hours after MCA occlusion. Glu attained its peak level after
20 minutes of ischemia and then rapidly declined to its baseline.
Butcher et al19 evaluated simultaneously the effect of
permanent MCA occlusion, with or without occlusion of the
lenticulostriate vessels, on the cortical and striatal amino acids of
rats. They demonstrated that proximal occlusion significantly elevated
neurotoxic amino acids in the striatum, while distal occlusion did not
cause these significant effects. However they reported a maximal
percent increase of Glu of 469% (n=4, P=NS), which was very
similar to our data. Hillered et al18 measured amino
acids, dopamine, and dopamine metabolites in the striatum of rats after
permanent MCA occlusion and showed dramatic increases in concentrations
of aspartate (Asp), Glu, Tau, GABA, and dopamine. However, Glu did not
decline to its baseline in their study, as found in our study. There
are four possibilities to explain this decrease.20 The
first possibility is that there is a decrease or cessation of Glu
release. A second possibility is the removal of amino acids by the
ongoing microdialysis itself, although this is unlikely because control
levels of Glu remain almost constant. The third possibility is the
removal of Glu into the circulating blood. The last possibility is that
Glu removal occurs due to an intact Glu uptake system. This is the most
reasonable hypothesis to explain this rapid decrease of Glu, because
there are significant increases in CBF in the lateral part of striatum
in this model.21
Hassler et al22 observed a decrease in Glu tissue concentrations in rats 1 week after unilateral premotor and motor cortex ablation. Shimada et al23 reported that extracellular Glu in cerebral cortex increased at CBF levels below approximately 20 mL/100 g per minute. They also suggested that the extracellular overflow of Glu is directly related to synaptic transmission. McGeorge and Faull24 studied the overall organization of the corticostriate projection in rat brains in detail and demonstrated that the sensory and motor areas project topographically onto the dorsolateral striatum. Perschak and Cuenod25 measured efflux of Glu and Asp in the striatum before, during, and after a 4-minute stimulation period of the ipsilateral frontal cortex. They observed that Glu and Asp were significantly elevated above the prestimulation resting concentration by 167% and 316%, respectively. Sensory and motor areas were affected by ischemia in our study,9 suggesting that neuronal depolarization might occur in the cerebral cortex, causing a release of Glu stored in vesicles. Accordingly, spiky Glu release could be detected only in the lateral part of the striatum. Increased concentrations of Tau,26 GABA,27 and dopamine1 28 29 could be an indirect response to Glu activation of specific receptors. Why did the levels of Tau, GABA and dopamine remain elevated when Glu declined to its baseline? Marsala et al30 reported that 20 minutes of reversible spinal cord ischemia caused transient Glu release and continuing Tau release and explained that prolonged Tau elevation corresponds to signs of irreversible changes on the ultrastructural level. Although no explanation is at hand, irreversible pathological damage could contribute to the discrepancy.
Delayed Neuronal Damage in Lateral Striatum
Histopathologic study clarified delayed neuronal damage in the
lateral part of the striatum. Why does neuronal damage occur in the
ipsilateral lateral part of the striatum? Kita et al21
studied regional CBF (rCBF) and local cerebral glucose metabolism in an
acute state using the same MCA occlusion model. They reported that 4
hours after MCA occlusion rCBF increased significantly whereas local
cerebral glucose metabolism decreased in the lateral part of the
striatum. This phenomenon may be associated with "luxury
perfusion."31 Olsen et al32 divided cases
of focal cerebral hyperemia into three groups: border-zone hyperemia,
postischemic hyperemia, and remote hyperemia. Hyperemia in this model
may refer to remote hyperemia. Recently
N-methyl-D-aspartate (NMDA) receptor
activation has been shown to lead to the generation of
endothelial-derived relaxant factor from neurons.33
Therefore, Glu release may lead to cerebral vasodilation and increased
rCBF in the striatum in this model, although the time point of rCBF
measuring is different. There are at least two different mechanisms of
ischemic brain injury: energy failure34 and postischemic
membrane perturbation.35 The breakdown of energy-producing
metabolism after decreased CBF leading to acute necrosis cannot be
explained by this phenomenon because of Kita's CBF study. In general,
the striatum is supplied by end arteries and represents the
ischemic core. The cortex is well endowed with collateral circulation
and may represent an ischemic penumbra.5 The
penumbra may particularly favor excitotoxicity. NMDA receptor–mediated
injury may be greater in the penumbra than in the ischemic core because
of greater Glu efflux, greater NMDA receptor channel complex
phosphorylation, higher pH, and greater oxygen
availability.36 The lateral part of the striatum in this
model is adjacent to the damaged cortex. We speculate that a massive
release of excitatory neurotransmitters may occur at the axon terminals
of the striatum, inducing neuronal damage. However, decrease of local
cerebral glucose metabolism in the striatum does not support the
hypothesis of excitotoxicity, since the time point of Glu release and
that of local cerebral glucose metabolism decline are different.
Nigrostriatal dopaminergic activity and glutamatergic activity have
been reported to play an important role in such striatal neuronal
damage.4 17 37 38 MK-801 has reduced 45Ca
accumulation in the striatum 7 days after MCA occlusion.9
We suggest that delayed neuronal damage in the lateral part of the
striatum may be regulated by the interactions of a variety of
neurotransmitters.
Alternatively, the recovery factor of the dialysis membrane for Glu was approximately 10%. Therefore, we think the extracellular concentration of striatal Glu during cortical ischemia is 30 µmol/L. On the other hand, a Glu concentration of 50 to 1000 µmol/L for a 5-minute period has been shown to cause irreversible cell loss in vitro.2 All dialysate samples were collected every 20 minutes in the present study. Shorter collection intervals might produce higher Glu concentrations.
Another mechanism for neuronal damage in the striatum is local damage caused by the focal spread of harmful agents such as acid metabolites. An acute metabolic acidosis localized in this region may be the most likely explanation of luxury perfusion.31 Analysis of dialysate in cases of neuronal damage due to other harmful agents is recommended for classification purposes.
Another possible mechanism for neuronal damage is vasogenic edema, which may originate from ischemic foci. In cases of cerebral infarction, extravasated plasma constituents spread outside the border of the infarct. The transport of plasma components and/or degradation products along nerve fiber tracts might add to the cerebral tissue damage by causing parenchymal changes in remote areas.39 Multifocal plasma extravasation is considered to be a major pathogenic factor for spontaneously occurring brain lesions in stroke-prone spontaneously hypertensive rats.40 Further detailed study is required to clarify this mechanism.
In conclusion, results from the present intracerebral microdialysis study suggest that neurotransmitter changes in the lateral part of the striatum differ from those in the medial part of the striatum after MCA occlusion in stroke-prone spontaneously hypertensive rats. The delayed neuronal damage that occurred in the lateral part of the striatum in this model may have been caused by massive Glu release that accompanied the dopamine release.
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Acknowledgments |
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The excellent technical assistance of Miwako Tatsumi is gratefully acknowledged.
Received May 12, 1994; revision received January 30, 1995; accepted February 20, 1995.
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  A. Melani, L. Pantoni, C. Corsi, L. Bianchi, A. Monopoli, R. Bertorelli, G. Pepeu, F. Pedata, and D. K. J. E. von Lubitz Striatal Outflow of Adenosine, Excitatory Amino Acids, {gamma}-Aminobutyric Acid, and Taurine in Awake Freely Moving Rats After Middle Cerebral Artery Occlusion : Correlations With Neurological Deficit and Histopathological Damage • Editorial Comment: Correlations With Neurological Deficit and Histopathological Damage Stroke, November 1, 1999; 30(11): 2448 - 2455. [Abstract] [Full Text] [PDF]
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