(Stroke. 1995;26:2333-2337.)
© 1995 American Heart Association, Inc.
Articles |
Differential Changes in 
- and ß-Adrenoceptors in the Cerebral Cortex and Hippocampus of the Mongolian Gerbil After Unilateral Brain Ischemia
From the Department of Pharmacology (H.K., S.U., F.I.) and the Second Department of Medicine (T.M., Y.N., A.K.), University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Correspondence to Hideyuki Kobayashi, PhD, Department of Pharmacology, Miyazaki Medical College, 5200 Kiyotake, Miyazaki 889-16, Japan.
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Abstract |
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Background and Purpose Changes in adrenoceptors in the cerebral cortex and hippocampus of Mongolian gerbils after brain ischemia were investigated.
Methods Twenty-four hours after unilateral occlusion of
the common carotid artery, 
1-, 2-, and
ß-receptors of the membrane fraction of the cerebral cortex or
the hippocampus were analyzed by binding assay with the use of
[3H]prazosin,
[3H]p-aminoclonidine, and
[125I]cyanopindolol as radioligands,
respectively.
Results In the cerebral cortex, the number of binding sites (Bmax) and the dissociation constant (Kd) of [3H]prazosin were not altered, whereas the Bmax value of [3H]p-aminoclonidine binding was decreased by 30% and that of [125I]cyanopindolol binding by 16% without a change in Kd values for the ligands. In the hippocampus, the Bmax values of [3H]prazosin, [3H]p-aminoclonidine, and [125I]cyanopindolol bindings were decreased by 21%, 53%, and 19%, respectively, but there was no change in the Kd values for the ligands. The bindings of [3H]prazosin and [3H]p-aminoclonidine of the contralateral side of the cerebral cortex and the hippocampus were not altered by ischemia, but that of [125I]cyanopindolol was decreased when compared with normal tissues.
Conclusions These results show that ischemia results in a
decrease in brain 1-, 2-, and
ß-adrenoceptors to various degrees, depending on the brain area
and the types of receptors, and suggest that vulnerability of the brain
to ischemia is different depending on brain areas and that the
regulatory mechanisms of 1-, 2-, and
ß-receptors are different.
Key Words: norepinephrine • cerebral ischemia • gerbils
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In comparison with other tissues, the brain is very vulnerable to ischemia because of its high metabolic rate despite the low oxygen stores and small reserves of high-energy phosphates or carbohydrates. Thus, ischemic insults result in a variety of functional changes in the central nervous system. Norepinephrine is a neurotransmitter of the adrenergic nervous system originating from the locus coeruleus, which innervates most parts of the brain and plays a role in a variety of higher brain functions such as emotions and moods. It is known that norepinephrine is massively released by ischemia.1 However, it is not known how the receptors for norepinephrine change after brain ischemia.
On the other hand, molecular mechanisms of the regulation of
adrenoceptors are becoming obvious. For example, treatment of rabbit
vascular smooth muscle cells with norepinephrine reduces
the number of 1-adrenoceptors, which is accompanied by a
rapid, but transient, downregulation of its mRNA.2 In the
case of 2-adrenoceptors, the number in HT29 cells and
opos-sum kidney cells3 4 is downregulated by agonist
treatment, whereas it is not clear how the receptors are regulated in
the platelet, liver, or fat cells, which contain abundant
2-adrenoceptors. In addition, stimulation of
ß-adrenoceptors also decreases the number of
ß-adrenoceptors by proteolytic degradation of the receptor
through protein phosphorylation5 as well
as by decreases in ß-adrenoceptor mRNA.6 7 These
processes involved in receptor regulation are ingeniously regulated by
second messengers, G-proteins, and protein
phosphorylation in tissue- and time-specific
manners.8 9 10
To provide a biochemical basis for functional changes in the brain by ischemia, we studied the changes in adrenoceptors after brain ischemia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male Mongolian gerbils weighing 40 to 60 g were used. This animal is widely used as a model of cerebral infarction because the formation of the circle of Willis is incomplete. The left common carotid artery was occluded by the use of 6-0 silk string under ether anesthesia. In the symptomatic animals, severe brain edema was observed 24 hours after ischemia. Adrenoceptors of nonoperated (normal), sham-operated, asymptomatic, and symptomatic animals were compared.
Twenty-four hours after occlusion of the carotid artery, the left and right cerebral cortex (entire gray matter) and the dorsal part of the hippocampus without entorhinal cortex were dissected from the brain and were homogenized by Biotron (level 9, 10 secondsx2) in 20 vol of 20 mmol/L Tris-HCl (pH 7.5) at 4°C. After centrifugation at 20 000g for 20 minutes, the pellet was washed twice more by centrifugation in the same buffer, and the final pellet was suspended in 20 vol of Tris-HCl buffer.
1-Adrenoceptors were measured with the use of
[3H]prazosin.11 The membrane fraction was
incubated in triplicate with 20 to 600 pmol/L of
[3H]prazosin in 50 mmol/L Tris-HCl buffer (pH 7.5) at
25°C for 15 minutes. The [3H]prazosin that was bound to
the membrane fraction was separated from the free ligand by filtration
through a GF/B glass fiber filter (Whatman), and the filters were
washed four times with 5 mL of cold 50 mmol/L Tris-HCl buffer. The
radioactivity was measured in the toluene base scintillation cocktail
with an efficacy of 45%. The specific binding of
[3H]prazosin was defined as the total binding minus the
nonspecific binding, which was determined in the presence of 10
µmol/L phentolamine.
2-Adrenoceptors were measured with the use of
[3H]p-aminoclonidine
([3H]PAC).12 The assay mixture consisted of
100 pmol/L to 3 nmol/L of [3H]PAC, 50 mmol/L Tris-HCl
buffer (pH 7.5), and the membrane fraction. Incubation was carried out
at 25°C for 30 minutes. The specific binding of [3H]PAC
was defined as the total binding minus the nonspecific binding, which
was determined in the presence of 10 µmol/L phentolamine.
ß-Adrenoceptors were measured with the use of [125I]cyanopindolol ([125I]CYP).13 The assay mixture consisted of 5 to 100 pmol/L of [125I]CYP, 50 mmol/L Tris-HCl buffer (pH 7.5), and the membrane fraction. Incubation was carried out at 37°C for 120 minutes. The specific binding of [125I]CYP was defined as the total binding minus the nonspecific binding, which was determined in the presence of 1 µmol/L (-)-propranolol.
The incubation times required to reach equilibrium of the bindings of
[3H]prazosin, [3H]PAC, and
[125I]CYP were 12 minutes, 15 minutes, and 90 minutes,
respectively. -Adrenoceptors were routinely assayed at a protein
content of approximately 75 and 100 µg protein in the cerebral
cortex and hippocampus, respectively. The specific bindings of
[3H]prazosin and [3H]PAC were linear,
with protein content up to at least 150 µg per tube.
ß-Adrenoceptors were routinely assayed at a protein content of
approximately 25 µg protein in both the cerebral cortex and
hippocampus, and the specific binding of [125I]CYP was
linear, with protein content up to at least 50 µg per tube.
Protein concentration was measured by the method of Lowry et al (1951).14
We performed statistical analyses with one-way ANOVA with post hoc mean comparison using the Newman-Keuls multiple range test. The Student's t test for group mean comparisons was used when only two means were compared.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After 24 hours of brain ischemia, half of the animals showed a turning behavior (repeated turning toward the side of the ligated artery) and torsion of the neck, and edema was observed in the occluded side of the brain of those animals. The remaining animals were asymptomatic. In the asymptomatic animals, there was no change in adrenoceptors in both the cerebral cortex and hippocampus (Table
). Therefore, only
symptomatic gerbils were used in the subsequent
experiments. There was no difference in the 1- and
2-receptors of the contralateral side of the
symptomatic animals from those of nonoperated (normal)
animals, and therefore the receptors of the ischemic side were
compared with those of the contralateral side (Table).
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Despite severe edema, the [3H]prazosin bindings to the
membrane fraction of the cerebral cortex were not changed by
ischemia (Fig 1). Scatchard analysis of
data showed that the binding parameters of the
contralateral and ischemic sides were almost identical
(Bmax: contralateral side, 139±11 fmol/mg protein, n=7;
ischemic side, 153±9 fmol/mg protein, n=7;
Kd value: contralateral side, 97±7 pmol/L;
ischemic side, 98±12 pmol/L.
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, control side; and 
,
ischemic side.
Ischemia induced significant reduction in the
[3H]PAC binding to the membrane fraction of the
cerebral cortex (Fig 2). The Bmax value was
reduced by 30% by ischemia (contralateral side, 222±15
fmol/mg protein; ischemic side, 156±6 fmol/mg protein;
P<.01, n=7), whereas Kd values were
not changed significantly (contralateral side, 668±65 pmol/L;
ischemic side, 648±92 pmol/L).
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[125I]CYP binding in the cerebral cortex was reduced in
both the ischemic and contralateral sides by ischemia
(Fig 3). The Bmax value in the
ischemic side was lower by 16% in comparison with normal
tissue and by 9% when compared with the contralateral side (normal
tissue, 131±3 fmol/mg protein, n=6; contralateral side, 121±4 fmol/mg
protein; P<.05 in comparison with normal tissue, n=4;
ischemic side, 110±3 fmol/mg protein; P<.01 in
comparison with normal tissue, n=4), whereas Kd
values were not changed significantly (normal tissue, 6.6±0.3 pmol/L;
contralateral side, 7.0±0.4 pmol/L; ischemic side, 6.2±0.3
pmol/L).
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, normal (nonoperated) tissue;
In the hippocampus, unlike in the cerebral cortex,
[3H]prazosin binding was decreased by the
ischemia. The Bmax value in the ischemic
side calculated by the Scatchard analysis decreased to 79% of
the control value (contralateral side, 100 fmol/mg protein;
ischemic side, 79 fmol/mg protein; 5 animals for each group,
means of two separate experiments), whereas the
Kd value was not changed (contralateral side,
176 pmol/L; ischemic side, 168 pmol/L; Fig 1
).
The decrease in the [3H]PAC binding to the hippocampus
was most dramatic; the Bmax value decreased by 53%
(contralateral side, 147 fmol/mg protein; ischemic side, 69
fmol/mg protein; 5 animals for each group, means of two separate
experiments) without a change in Kd value
(control side, 535 pmol/L; ischemic side, 588 pmol/L; Fig 2).
The Bmax value of the [125I]CYP binding
to the hippocampus was decreased by 19% in comparison with normal
tissue and by 14% when compared with the contralateral side (normal
tissue, 85±2 fmol/mg protein, n=5; contralateral side, 80±3 fmol/mg
protein, n=5; ischemic side, 69±5 fmol/mg protein;
P<.05 in comparison with normal tissue, n=5) without a
change in the Kd value (normal tissue, 9.6±0.4
pmol/L; contralateral side, 10.4±0.3 pmol/L; ischemic side,
10.2±0.6 pmol/L; Fig 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study we showed the changes in
1-,
2-, and ß-adrenoceptors in the cerebral cortex and
hippocampus after 1 day of unilateral occlusion of the common carotid
artery. These adrenoceptors are abundantly present in the cerebral
cortex and hippocampus, with higher density in the cerebral cortex than
in the hippocampus.15 16 17 The change in
2-adrenoceptors, which have been first identified as
presynaptic autoreceptors but are also present as postsynaptic
receptors in the brain, was largest among adrenoceptors by
ischemia.18 The differential alterations of the
receptors or more importantly, the persistence of
1-receptors in the cerebral cortex, which do not change
after ischemia, would suggest that the observed changes in the
receptors are not simply due to the general degradation of the neurons.
Furthermore, our results suggest that the mechanisms that regulate the
receptors are different among various types of receptors, and the
vulnerability of the cells to ischemia is also different. Ischemia causes a number of changes that may lead to a change in the number of adrenoceptors. These are changes in release of transmitters,19 including norepinephrine, levels of second messengers such as cyclic AMP,20 protein kinase,21 and the capacity for protein and RNA synthesis.22
There are many changes induced by ischemia that may not have
functional significance, and the possibility that the changes in
adrenoceptors observed in this study are those kinds of changes could
not be ruled out. However, none of the 1-,
2-, and ß-adrenoceptors in the
asymptomatic gerbils were changed by ischemia.
Thus, signs such as hemiparesis, declination, ptosis, cervical torsion,
convulsion, and muscle weakness might be in part related to the
selective reduction of the adrenoceptors observed in this study. The
elucidation of the relationship of the changes in adrenoceptors and
brain function may provide us with a clue for treatment of the brain
dysfunction that occurs after ischemia.
Cerebral blood flow was reported to be reduced to one tenth that of normal animals by ischemia, from 1.10±0.08 to 0.11±0.03 mL/g per minute in the cerebral cortex and from 0.58±0.02 to 0.04±0.01 mL/g per minute in the hippocampus in symptomatic animals.23 Motor deficits in the symptomatic gerbils were likely due to the reduction of blood flow in the forebrain, since cerebellar blood flow does not reduce19 or moderately reduces only in a subpopulation of animals24 by occlusion of the carotid artery in this species.
1- and 2-receptors in the contralateral
side of the ischemia did not decrease, but there was a decrease
in ß-receptors by carotid occlusion. A similar decrease in the
contralateral side occurs in ß-receptors in the cerebral
microvessels by ischemia.25 26 In the case of the
microvessels, the disruption of nerve pathways connecting the
hemispheres by the transection of the corpus callosum partially
reverses the decreasing effect of carotid occlusion on
ß-receptors in the contralateral side. In addition, the
destruction of the adrenergic neurons by an
intraventricular injection of
6-hydroxydopamine abolished the effect of
ischemia on the ß-receptors of microvessels of both
hemispheres. These results suggest that ß-receptors in the
cerebral microvessels are partially regulated by neuronal activity. In
the present study, mechanisms that caused the decrease in
ß-receptors in the contralateral side were not known, but similar
mechanisms observed in the cerebral microvessels may be the reason for
the regulation of ß-receptors in the brain tissue.
Changes in neurotransmitter receptors such as muscarinic cholinergic
receptors,27 28 29 
-aminobutyric acid
receptors,30 N-methyl-D-aspartate
receptors,31 and opioid receptors32 were
studied after transient ischemia in correlation with tardive
neuronal death. From the clinical point of view, brain ischemia
produced by embolism persists for a long period. Thus, the changes in
the receptors observed in this study may provide, for the first time, a
biochemical basis for abnormal neurotransmission after
ischemia.
Neurotransmitters have become recognized as important factors in the development of neuronal damage after ischemia.33 Norepinephrine has been reported to have both protective34 35 36 and deteriorative37 38 effects on the brain after ischemia. Our data showed that a number of receptors for norepinephrine were changed after ischemia, which suggests that the modulatory action of norepinephrine on neural damage is changed by ischemia. The treatment to modify adrenergic transmission may become a useful strategy for the treatment of brain ischemia.
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Acknowledgments |
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This study was supported in part by a grant-in-aid from the Ministry of Education, Science, and Culture of Japan (04671423) (Dr. Kobayashi). The authors thank Professor Shinichi Oishi for critical revision of the manuscript.
Received June 23, 1995; revision received September 13, 1995; accepted September 13, 1995.
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