(Stroke. 1995;26:312-317.)
© 1995 American Heart Association, Inc.
Articles |
Collagenase-Induced Intrastriatal Hemorrhage in Rats Results in Long-term Locomotor Deficits
From the Departments of Neurosurgery and Physiology, Program in Neuroscience, University of Minnesota Medical School, Minneapolis.
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Abstract |
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Background and Purpose Previous studies have shown that injection of the metalloproteinase collagenase directly into the caudate nucleus of rats causes an intracerebral hemorrhage. The purpose of the present study is to determine functional deficits associated with a collagenase-induced hemorrhagic lesion of the striatum.
Methods Twelve adult rats received a 2-µL infusion of bacterial collagenase (0.5 U in saline) into the right striatum. The rotational response to apomorphine (1 mg/kg SC) administration was then examined at 1, 4, 7, 21, 35, and 70 days after the surgery. In addition to the rotational asymmetry studies, the initiation of stepping movements in each forelimb was determined 8 weeks after the collagenase injections. In the assessment of rotational asymmetry and stepping ability, an additional six control animals received unilateral injections of saline alone. After behavioral testing, brains were processed for neuropathological evaluation.
Results A net ipsilateral rotation was noted at all posthemorrhage time periods. The average rotational asymmetries on these days were 14.57±2.9, 20.33±2.7, 19.99±4.4, 18.95±4.9, 17.03±4.9, and 14.4±4.7, respectively (data expressed as mean clockwise rotations per 5 minutes ±SEM). The average number of steps initiated by the forelimb ipsilateral and contralateral to the lesion was 28.3±2.1 steps per minute and 13.6±1.5 steps per minute, respectively. This difference between left and right forelimb stepping was stable and reproducible for 3 consecutive days. Histological studies revealed a long-lasting hematoma cavity surrounded by dense reactive gliosis in the striatum.
Conclusions We conclude that collagenase-induced intrastriatal hemorrhage results in long-term locomotor deficits and is therefore a useful model for developing and assessing therapeutic approaches for the restoration of neurological function after intracerebral hemorrhage.
Key Words: animal models • cerebral hemorrhage • corpus striatum • motor deficit • rats
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Introduction |
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Intracerebral hemorrhage (ICH) is a major cause of morbidity and mortality and constitutes approximately 10% of all cerebrovascular accidents.1 Nearly 14% of all deaths attributed to cerebrovascular disease in the United States can be attributed to intracerebral hemorrhage.2 Various studies have shown a strong relation between ICH and age.3 4 The incidence of ICH (21% to 48%) in stroke-related disorders was reported to be much higher in some ethnic populations such as the Chinese and Japanese.5 6 7 8 9 The most recent report revealed that the annual incidence of ICH (15/100 000 population) is more than twice as common as subarachnoid hemorrhage, and the mortality rate (44% at 30 days) is just as deadly as subarachnoid hemorrhage.10 Despite the high incidence of ICH, there has been a paucity of clinical and laboratory research focused on this cerebrovascular disorder.
The development of a suitable animal model would greatly facilitate the study of ICH and would be useful for evaluating novel strategies to restore neurological function. Although a number of experimental models have been used to study ICH,11 12 13 14 15 16 17 18 these models have been limited because of poor reproducibility of the hematoma and lack of long-lasting neurological deficits.
Rosenberg et al19 recently described an animal model in which a hemorrhagic lesion was produced by infusing bacterial collagenase into the caudate nucleus of rats. Collagenase directly injected into the brain parenchyma causes the disruption of blood vessels of basal lamina, leading to extensive bleeding without tissue necrosis. In addition, the hematoma size is dose dependent and reproducible. In the present study we characterized the deficits in locomotor function associated with this model of ICH. We found long-lasting deficits in rotational bias and forelimb stepping. The permanent nature of these motor impairments suggests that this experimental model of ICH may be useful in evaluating novel approaches in preventing hemorrhage-induced brain injury and approaches targeted at repairing damaged neural connections in attempts to restore function.
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Materials and Methods |
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Male Sprague-Dawley rats (weight, 250 to 300 g) were anesthetized with sodium pentobarbital (50 mg/kg IP) (Nembutal, Abbott Labs) and placed in a Kopf stereotaxic apparatus. A midline incision was made through the scalp to expose the skull. An injection was made stereotaxically into the striatum with a 10-µL Hamilton syringe at the following coordinates: 0.4 mm anterior and 3.0 mm lateral to bregma and 5.0 mm ventral to the cortical surface. Body temperature was maintained at 37°C with a CMA/150 temperature controller throughout the surgery. The sham group (n=6) received a 2-µL injection of saline. The experimental group (n=12) received a 2-µL injection of saline containing 0.5 U bacterial collagenase (type VII, Sigma Chemical Co). The infusion rate for both groups was 0.2 µL/30 s. Once the infusion was complete, the Hamilton syringe was left in place for 5 minutes. The rats recovered from surgery in a cage containing food and heated by an incandescent light bulb.
The animals were tested for rotational behavior in response to apomorphine the day after surgery. Each rat was placed in a clear Plexiglas cylinder 72.5 cm in diameter and 67 cm tall. Apomorphine (1 mg/kg, dissolved in sterile saline) (Sigma) was injected subcutaneously, and rotations were determined by a computer-controlled Columbus Instruments Videomex-V system. Counts were taken every 5 minutes after injection and continued for 60 minutes. This was repeated on days 4, 7, 21, 35, and 70 after surgery. On days 14, 28, 42, and 77 after surgery, animals were tested for amphetamine-induced rotation. Amphetamine (5 mg/kg, dissolved in sterile saline) (Sigma) was injected intraperitoneally, and counts were taken every 5 minutes for a 90-minute period. The sham-operated control rats were also tested for rotational behavior in response to apomorphine on days 1, 7, and 70.
Step initiation was assessed in both the experimental group (n=11) and the sham group (n=6) on days 56, 57, and 58 by independently analyzing stepping behavior in the left and right forelimbs. In this test the rat is held in a manner that restrains one forelimb and both hind limbs. The free limb is placed on a flat surface so that the body weight of the animal is centered over the limb. The rat initiates a stepping movement, and the investigator adjusts the position of the rat so that the body weight of the animal is again centered over the limb. In this manner, the number of steps initiated by each limb was counted during a 1-minute period. Data were recorded as steps per minute.
After behavioral testing, rats were injected with an overdose of anesthesia (pentobarbital, 50 mg/kg IP) and then perfused through the ascending aorta (the cannula was inserted through the left ventricle) at 110 to 120 mm Hg of pressure, with the following solutions: (1) 0.1 mol/L potassium phosphate buffer (Sigma) and 0.002% calcium chloride (Mallinckrodt Chemicals) for 2 minutes; (2) 2% paraformaldehyde (pH 6.5) (Sigma), 0.002% calcium chloride, and 0.02% glutaraldehyde (Sigma) for 3 minutes; and (3) 2% paraformaldehyde (pH 8.5), 0.002% calcium chloride, and 0.02% glutaraldehyde for 30 minutes. Brains were then removed and stored in 2% paraformaldehyde (pH 8.5) without glutaraldehyde for at least 24 hours. Brains were cut into 40-µm sections on a microtome, and the sections were stored in 0.1 mol/L potassium phosphate buffer. The sections were stained with thionin solution (Fisher Scientific Co) for histopathological examination.
The adjacent slices were also stained with use of antibodies that recognize glial fibrillary acidic protein (GFAP). The sections were incubated in the following steps: (1) endogenous peroxidase blocking by peroxidase (3% in distilled water for 10 minutes); (2) normal goat serum blocking (1:20, 10 minutes); (3) rabbit anti-GFAP (Chemicon, at room temperature for 1 hour); and (4) goat anti-rabbit IgG followed by rabbit peroxidase-antiperoxidase complex with use of a PAP kit (BioGenix Lab). For the peroxidase reaction a DAB kit (Vector) was used.
All data shown are expressed as mean±SEM. An ANOVA followed by post hoc pairwise comparisons for data from the behavior study was used to assess the significance of the difference in rotational asymmetry and in stepping behavior between control and ICH animals. All protocols for surgery and behavioral testing were reviewed and approved by the Research Animal Resources Institutional Review Board of the University of Minnesota.
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Results |
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Of the 12 adult rats that received a 2-µL infusion of bacterial collagenase, 1 died prematurely (1 week after surgery), and further studies were carried out with the 11 remaining animals in the ICH group. A net ipsilateral rotation in response to apomorphine administration was noted in the experimental group. Seven days after surgery, average rotational response to apomorphine was observed to peak at 10 to 20 minutes after injection (Fig 1
). Net
rotations were analyzed for the first 30 minutes after drug
administration. The rotational asymmetry induced by apomorphine was
maintained throughout the entire 70-day period of testing as follows:
day 1, 14.57±2.9; day 4, 20.33±2.7; day 7, 19.99±4.4; day 21,
18.95±4.9; day 35, 17.03±4.9; and day 70, 14.4±4.7, all per 5
minutes (Fig 2). Interestingly, the rotational
response was greater on day 4 than on day 1. This may be due to the
effects of anesthesia used during surgery, which may have attenuated
the general responses of motor activity, leading to lower rotational
responses on day 1. No significant rotational asymmetry was observed in
the control group.
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) and intracerebral hemorrhage
lesioned rats (
) for 60 minutes after apomorphine (1 mg/kg SC)
injection (n=6 for control rats and n=11 for lesioned rats).
*P<.05 for intracerebral hemorrhage vs
control rats. R-L indicates right to left.
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Amphetamine and apomorphine studies were conducted on alternating weeks
to prevent the effects of drug interactions and sensitization by
repeated injections over short time periods.20 21 Although
a strong ipsilateral rotational response to amphetamine was observed 14
days after surgery (31.1±8.1/5 min), this response progressively
decreased such that there were no significant rotations by day 77
(Table).
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Eight weeks after surgery, the ability of an animal to initiate
stepping movements was assessed. The left forelimb initiated
significantly fewer steps than the right forelimb (13.8±0.8 versus
29.4±1.0; P<.0001) (Fig 3) in animals
with unilateral striatal ICH. In contrast, no significant difference
was observed between the right and left forelimbs of control animals
(25.0±1.5 versus 27.8±1.0; P=.13). In addition, the number
of steps initiated by either forelimb in the control group was similar
to that of the right forelimb in the experimental group.
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Thionin staining revealed a large cystic formation consistently located
within the striatum (Fig 4, top left).
The anterior part of the striatum, at the level 1.6 to 2.0 mm rostral
to bregma, was mostly intact. At the level of the injected site, only a
tiny remaining striatum surrounding the cystic cavity was observed.
Under high-power magnification, the border of the cystic cavity was
abrupt. Only the area at 80 to 120 µm from the cavity wall showed
significant pathological changes, in which there were accumulated
polymorphonuclear leukocytes (Fig 4, top right). The lateral ventricle
ipsilateral to the lesion was markedly enlarged because of the severe
atrophy of the striatum.
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GFAP staining revealed diffuse and dense reactive gliosis in the
remaining striatum (Fig 4
, bottom panel). The density of reactive
astrocytes was higher in the area close to the hematoma cavity,
sometimes forming a glial wall of GFAP-positive processes. These
GFAP-positive astrocytes also showed a radiating pattern of processes
from the hematoma site. Large numbers of radially aligned GFAP-positive
astrocytes were observed in the corpus callosum and extending into the
contralateral side. There were also GFAP-positive astrocytes that were
faintly stained with a thin cell body in the cortex ipsilateral to the
lesion and in the striatum contralateral to the lesion. These
observations were a consistent finding among all brains examined. In
the control animals only the area close to the needle tract showed very
few GFAP-positive astrocytes.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A number of experimental animal models have been used to study the etiology of ICH and to assess strategies for restoring neurological function. For example, the induction of a mechanical mass lesion by means of inflating a microballoon within the brain parenchyma has been used to assess the change of regional cerebral blood flow,11 12 somatosensory evoked potentials,13 and intracranial pressure.11 18 Although this model is useful for studying the mass effects of an ICH, it does not address the consequences of direct contact between blood and brain parenchyma. Plasma components infiltrating into brain tissue can cause cerebritis22 and leukocytic infiltration. In addition, proteolytic enzymes and hemoglobin-driven oxidation can mediate direct injury within the central nervous system (CNS).23 Sadrzadeh et al,24 for example, found that purified hemoglobin not only inhibits Na,K-ATPase activity in CNS homogenates but also catalyzes peroxidation of CNS lipids. An in vivo model that mimics both physical and biochemical effects of ICH would be useful.
Direct injection of autologous blood into the brain parenchyma has been used to simulate ICH.14 15 16 17 18 Injection of blood into the brain parenchyma, however, often results in the dissection of tissue, with slitlike lesions through the white matter, leading to ventricular rupture. Histopathological findings also reveal varying degrees of hematoma size.14 15
More recently, Rosenberg et al19 observed that direct injection of the metalloproteinase collagenase into the caudate nucleus of rats causes an ICH. The brain showed prolonged edema,19 25 and they concluded that the pathological changes observed in their model were consistent with those reported in human patients with ICH. With respect to neurological assessment, despite the considerable size of the lesion in the striatum, Rosenberg and colleagues were unable to detect a long-term behavioral deficit using a behavioral rating scale. In fact, experimental rats improved to near control levels by 21 days after collagenase infusion into the striatum. In this study they showed that the recovery of behavior abnormality began by 72 hours, which may be related to the acute nature of brain edema.19
Damage to the striatum after experimental ICH in some ways resembles that found in experimental Huntington's disease. Unilateral lesions of the striatum by direct injections of glutamate analogues and excitotoxins such as kainic acid, ibotenic acid, and quinolinic acid result in selective intrastriatal cell damage26 27 28 29 30 31 and consequently have been used extensively as a model for Huntington's disease.26 31 32 33 34 35 36 Rotational behavior resulting from the unilateral administration of these excitotoxins into the striatum is induced by dopaminergic agonists and compounds that enhance dopamine release, such as apomorphine and amphetamine, respectively.28 32 33 35 37 An observed reduction of apomorphine-induced ipsilateral turning has been considered to reflect the amelioration of rotational bias.26 35 37 38
In our study the direction of the rotational bias in relation to the side of the ICH in the striatum is similar to that noted for kainic acid lesions28 and ibotenic acid lesions.35 The rotational responses in this ICH model were maintained throughout 70 days of testing. The collagenase-induced ICH model should therefore prove useful as a means to assess different strategies for restoring functional integrity in patients with ICH.
Amphetamine has also been used to induce rotational bias in rats that have received intrastriatal injections of excitotoxins.26 35 Using amphetamine, these researchers observed rotational behavior at 7 months after the lesion. In the present study a net ipsilateral rotation in response to amphetamine was observed 14 days after collagenase infusion. However, this response sharply declined throughout the 70 days of testing. Since amphetamine enhances dopamine release, the progressive amelioration of ipsilateral rotational bias as observed with amphetamine administration may reflect the recovery from a transient inhibition of release related to cerebral edema.19 The mass effect of edema may also cause temporary dysfunction in the nucleus accumbens, which is known to amplify locomotor and rotational behavior in rodents.39 Alternatively, other dopaminergic pathways such as the nigropallidal projection, which is known to be involved with rotational behavior,40 may sprout or become upregulated in the hemorrhage side of the brain after dysfunction of the nigrostriatal pathway. Thus, systemically administered amphetamine may result in dopamine secretion to activate motor components of the basal ganglia in a bilateral fashion.
We also carried out a stepping behavior study for the assessment of motor asymmetry without pharmacological manipulation. Schallert et al38 recently described this method for examining motor behavior in rats with unilateral 6-hydroxydopamine lesions. They reported that while the forelimb ipsilateral to the lesion side is capable of initiating stepping movements, the contralateral forelimb can only make "catch-up" steps. They hypothesize that the inability to initiate movement may reflect akinesia seen in patients with Parkinson's disease and that improvement of this deficit may be a useful target of therapy. In the present study the tendency for an experimental animal to initiate a stepping movement with the contralateral forelimb was approximately 50% that of the ipsilateral forelimb. This deficit was also observed 8 weeks after collagenase infusion. Our assessment of stepping behavior was conducted by an unblinded observer and is thus a potential source of bias. Although deficits in stepping behavior were quite dramatic in animals with lesions, future studies that use this test should consider a blinded assessment to minimize potential bias of data.
Our histological studies showed a long-lasting hematoma cavity surrounded by dense gliosis, which is often seen in the brains of ICH patients several years after bleeding. It is noteworthy that there were GFAP-positive astrocytes not only in the lesioned striatum but also in the striatum contralateral to the lesion, which is in agreement with a previous study that used excitotoxins in the striatum.41 The histopathological similarities of this experimental model to ICH patients make it possible to assess long-term degenerative and regenerative processes in the brain after the onset of ICH.
We conclude that collagenase-induced intrastriatal hemorrhage results in locomotor deficits that are both long-term in nature and reproducible. It should therefore provide a useful model for developing strategies for the restoration of neurological function after ICH.
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Acknowledgments |
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This study was supported in part by Public Health Service grant RO1-NS-24464 (Dr Low), a fellowship from the American Heart Association (Dr Kondoh), and an American Heart Association Established Investigator Award (Dr Low). The authors wish to thank Joan Aanderud and Linda King for their expert clerical and administrative assistance and Mike McPhee for technical assistance.
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Footnotes |
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Reprint requests to Walter C. Low, PhD, Department of Neurosurgery, 421 Lions Research Bldg, University of Minnesota Medical School, 2001 Sixth St SE, Minneapolis, MN 55455.
Received April 26, 1994; revision received September 26, 1994; accepted October 21, 1994.
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