(Stroke. 1997;28:1430-1436.)
© 1997 American Heart Association, Inc.
Articles |
CP-0597, a Selective Bradykinin B2 Receptor Antagonist, Inhibits Brain Injury in a Rat Model of Reversible Middle Cerebral Artery Occlusion
From Cortech Inc, Denver, Colo.
Correspondence to Virginia Beckey, Cortech Inc, Denver, CO 80221. E-mail gbeckey{at}crtq.com
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Abstract |
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Background and Purpose Recent studies demonstrated a significant neuroprotective action of the selective peptide-based bradykinin B2 receptor antagonist CP-0597 after permanent middle cerebral artery (MCA) occlusion (MCAO) in the rat. We therefore evaluated the efficacy of this compound after reversible MCAO in the rat.
Methods Male Wistar rats underwent reversible MCAO by insertion of a nylon monofilament to the origin of the MCA. After 1 hour the filament was retracted and the ischemic tissue reperfused. Immediately after MCAO, primed miniosmotic pumps containing either vehicle or CP-0597 (300 ng/kg per minute) were implanted into the subcutaneous space (n=14 per group). Twenty-four hours after surgery, animals were killed and brains fixed, and 4-µm sections were taken from five sequential tissue blocks labeled A through E and stained with hematoxylin and eosin. Clinical evaluation of rats was performed by neurological scoring and change in body weight.
Results Treatment with CP-0597 significantly reduced percent increase in hemisphere size of the ischemic hemisphere in all brain sections (C section: vehicle, 40.6±4.3% versus CP-0597, 20.8±5.3%; P<.001), total infarct volume (vehicle, 206.5±7.7 mm3 versus CP-0597, 94.0±19.2 mm3; P<.001), cortical infarct volume (vehicle, 145.5±4.5 mm3 versus CP-0597, 64.0±15.1 mm3; P<.001), subcortical infarct volume (vehicle, 55.8±4.1 mm3 versus CP-0597, 27.5±4.5 mm3; P<.001), and the number of necrotic neurons (vehicle, 42.9±3.8 versus CP-0597, 23.6±4.7 per field; P<.01). Neurological score (vehicle, 2.78±0.36 versus CP-0597, 6.29±0.87; P<.01) and change in body weight (vehicle, -28.7±2.0 g versus CP-0597, -18.2±2.8 g; P<.01) were also significantly improved.
Conclusions The present data demonstrate the significant overall efficacy profile of CP-0597 in a rat model of reversible MCAO and provide strong rationale for the use of such a bradykinin B2 receptor antagonist in the treatment of stroke.
Key Words: bradykinin • brain edema • cerebral ischemia, focal • neuroprotection • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Bradykinin is an important mediator of the inflammatory response in both the periphery1 and the central nervous system.2 All the components of the kallikrein/kinin system3 4 and particularly tissue kallikrein have been identified in brain tissue from various species.3 4 The actions of bradykinin are mediated through B1 (inducible) and B2 (constitutive) receptor subtypes.5 6 Both receptors are involved in inflammatory responses and share a similar pattern of distribution throughout the body.5 6 B1 and B2 receptors have been localized in various regions of the rat, guinea pig, and bovine central nervous system7 8 9 10 11 and visualized on human brain neurons.12
Many of the physiological actions of bradykinin are common to pathological phenomena occurring after a cerebral ischemic insult. Bradykinin stimulates the production and release of eicosanoids, cytokines, nitric oxide, free radicals, and excitatory amino acid neurotransmitters,1 13 14 15 16 the latter directly resulting in an in- crease in neuronal intracellular calcium levels.16 Release of such mediators results in cerebral arterial dilatation, loss of cerebrovascular autoregulation, endothelial cell lesions, increased capillary permeability, and breakdown of the blood-brain barrier, causing vasogenic edema formation17 18 and ultimately neuronal injury and death.2
Inhibition of the actions of bradykinin has been shown to reduce brain edema after global ischemia19 or cold lesion trauma18 in the rat and reduce intracranial pressure in humans after traumatic brain injury.20 We have recently demonstrated that the bradykinin B2 receptor is involved in the pathogenesis of cerebral ischemic injury and that the selective B2 receptor antagonist CP-0597 significantly inhibits brain infarction in a rat model of permanent MCAO.21 This compound has been shown to be a potent and selective bradykinin B2 receptor antagonist with a long duration of action after intravenous or subcutaneous administration in rat and rabbit and to be highly resistant to degradation by a variety of protease enzymes in vitro.22 The objective of the present study was to determine the potential therapeutic value of CP-0597 by investigating the effects of this B2 receptor antagonist in a rat model of rMCAO, a system that closely pertains to the human condition of stroke.
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Materials and Methods |
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All experiments were conducted according to the guidelines of the Institutional Animal Care Committee. Animals were housed at 21°C with free access to food and water.
Reversible focal cerebral ischemia was induced as described previously.23 Briefly, male Wistar rats (weight, 270 to 300 g) were anesthetized with halothane (2% in O2) (Halocarbon Labs), and the right external carotid artery was exposed through a midline incision. MCAO was produced by insertion of a 4-0 nylon monofilament (Ethicon Inc) precoated with poly-L-lysine (Sigma) into the right external carotid artery, through the internal carotid artery to the origin of the MCA. After 1 hour the filament was retracted to allow reperfusion of the ischemic region. Body temperature was maintained at 37±0.5°C throughout surgery with the use of a heating pad. The same surgical procedure was applied to sham-operated animals with immediate retraction of the occluding nylon monofilament after insertion to the origin of the MCA.
Rats were treated with either vehicle or CP-0597, a bradykinin B2 receptor antagonist, by continuous subcutaneous infusion through miniosmotic pumps (Alza Corp) (n=14 per group). CP-0597 is a potent, stable, long-acting, and selective bradykinin B2 receptor antagonist.22 Primed miniosmotic pumps containing vehicle or CP-0597 were implanted into the subcutaneous space at the scruff of the neck immediately after MCAO. Pumps released 300 ng/kg per minute CP-0597 or vehicle at a rate of 8 µL/h over the ensuing 24-hour period. All treatments were administered in a blinded fashion.
Twenty-four hours after MCAO, animals were anesthetized with sodium pentobarbital (60 mg/kg IP) and transcardially perfused with 50 mL heparinized isotonic saline followed by 50 mL Bouin's solution (Sigma). Brains were removed and stored in Bouin's solution for at least 48 hours before histopathological analysis.
Histopathological analysis was performed on fixed brains that were sectioned into sequential 2-mm blocks labeled A through E. The stereotaxic coordinates of sections cut from tissue blocks A through E were approximately as follows: A=+4.2, B=+1.7, C=+0.2, D=-1.3, and E=-3.3 with respect to bregma. Tissue blocks were embedded in paraffin, and 4-µm sections were cut from each block and stained with H&E. Brain sections were analyzed for brain edema, infarct size, and the number of necrotic neurons in defined regions of the brain.
Brain edema was quantified by measurement of the percent increase in hemisphere size of the right damaged hemisphere compared with the left undamaged hemisphere in sections A through E with the use of Sigma scan image analysis (Jandel Scientific), as reported previously.24 Brain infarction, defined as the area of pallor on each section (A through E), was charted onto stereotaxic maps, to adjust for enlargement of infarcted tissue due to brain swelling, and quantified by Sigma scan image analysis. Neuronal counts were performed at x20 magnification to determine the number of necrotic neurons in defined cortical and subcortical regions of sections taken from tissue block C corresponding to the level of the anterior commissure.
Clinical evaluation of rats was performed by neurological scoring of
forelimb flexion, symmetry of movement and forepaw outstretching
(Table
), and change in body weight over the experimental
period. Neurological evaluation was performed in conscious rats before
surgery, 30 minutes after arterial occlusion (ie, 30
minutes before reperfusion), and immediately before the rats were
killed. We used three tests that were adapted from previously published
reports showing the correlation between behavioral responses and
neurological outcome after focal cerebral
ischemia.24 25 The neurobehavioral tests consisted
of the following. (1) In the forelimb flexion test, the rat was held in
the air by the tail, and the degree of left forelimb flexion was scored
between 0 and 3. (2) In the duration of forelimb flexion test, the rat
was held in the air by the tail, and the score (0 to 4) was determined
by the duration of left forelimb flexion during a 10-second period. (3)
In the symmetry of movement/forepaw outstretching test, the rat was
made to walk along the bench on its forelimbs while being held by the
tail to keep the hindlimbs in the air. Symmetry in forepaw
outstretching was observed and scored (0 to 3) (Table). Rats were
scored on a ranking scale of 0 to 10, which reflects the cumulative
score of the individual tests, with a score of 10 reflecting normal
behavior. Rats that did not exhibit behavioral deficits before
reperfusion were excluded from the study (<10%). Body weight was
recorded before surgery and before the rats were killed.
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In separate studies MABP was measured by pressure transduction through an indwelling cannula inserted into the femoral artery under halothane anesthesia (2% in O2). The femoral catheter was connected to a pressure transducer, and MABP was recorded on a Grass polygraph recorder (model 79D). Rats were under anesthesia for the duration of the experiment, and core body temperature was recorded every 10 minutes by insertion of a rectal probe (Cole-Palmer Instrument Co), 5 cm beyond the rectum. MABP and core body temperature were recorded for 30 minutes before MCAO, during arterial occlusion, and for 2 hours after reperfusion. Animals received either vehicle (n=4) or CP-0597 (300 ng/kg per minute; n=4) through a primed miniosmotic pump implanted into the subcutaneous space immediately after MCAO.
Results are presented as mean±SEM. Statistical differences between groups were assessed with Student's t test for parametric data and the Mann-Whitney U test for nonparametric data. A value of P<.05 was considered statistically significant.
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Results |
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MCAO for 1 hour followed by 23 hours of reperfusion resulted in extensive and reproducible hemispheric swelling and focal infarction throughout cortical and subcortical structures quantified 24 hours after MCAO. All animals (n=14 per group) that underwent MCAO displayed behavioral deficits before reperfusion of the ischemic territory.
Treatment with the selective bradykinin B2 receptor
antagonist CP-0597 significantly reduced the percent
increase in ischemic hemisphere size compared with the
contralateral undamaged hemisphere in brain sections A through E (Fig 1). The size of the contralateral hemisphere did not
differ from either ipsilateral or contralateral values of hemisphere
size in sham-operated rats (data not shown). Vehicle-treated rats
exhibited a mean increase in hemisphere size of 40.6±4.3% in the
damaged hemisphere (section C). In the corresponding section of
CP-0597–treated rat brain, mean hemispheric enlargement was limited to
20.8±5.3% (P<.01, unpaired Student's t test).
Histological staining of brain sections with H&E
revealed that vehicle-treated animals consistently sustained
extensive lesions to cortical and subcortical structures, including the
basal ganglia illustrated in the photomicrographs of Fig 2. Infarct size was dramatically reduced in all regions
after treatment with CP-0597 (Fig 2). Quantification of infarct size
demonstrated the reproducible nature of brain infarction in sections A
through E and the significant reduction in infarct size observed after
CP-0597 treatment at each level examined (C section values: vehicle,
28.2±1.6 mm2 versus CP-0597, 15.6±2.6
mm2) (Fig 3A). Total infarct volume was
significantly reduced in CP-0597–treated rats (94.0±19.2
mm3) compared with vehicle-treated controls
(206.5±7.7 mm3; P<.001, unpaired
Student's t test) (Fig 3B). Analysis of the degree
of cortical and subcortical infarction showed significant protection in
both regions with CP-0597 treatment (cortical infarct volume: vehicle,
145.5±4.5 mm3 versus CP-0597, 64.0±15.1
mm3; P<.001; subcortical infarct volume:
vehicle, 55.8±4.1 mm3 versus CP-0597, 27.5±4.5
mm3; P<.001, unpaired Student's t
test) (Fig 3B). At high magnification (x100) the number of necrotic
neurons in specifically defined regions of tissue block C (Figs 4 and 5) were quantified. Treatment with
CP-0597 significantly reduced the number of necrotic neurons per field
in all four regions assessed (Fig 5) (area II, section C: vehicle,
42.9±3.8 versus CP-0597, 23.6±4.7 per field; P<.01,
unpaired Student's t test).
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Clinical evaluation of rats was performed before surgery, 30 minutes
after MCAO, after recovery from anesthesia and before
reperfusion, and again immediately before the rats were killed. All
animals scored normally (10) before surgical manipulation. Mean
postocclusion/prereperfusion neurological score was similar in both
vehicle (2.45±0.16) and treated (2.48±0.16) groups when animals
showed severe contralateral hemiparesis manifested most clearly as
marked left forelimb flexion and a tendency to circle. Twenty-four
hours after MCAO, animals treated with CP-0597 showed a dramatic
improvement in behavioral parameters (6.29±0.87) compared
with vehicle-treated controls, which appeared to sustain neurological
deficits similar to those observed before reperfusion (2.78±0.36;
P<.01, Mann-Whitney U test) (Fig 6A). Change in body weight over the experimental period
was significantly improved in animals treated with CP-0597 (-18.2±2.8
g) compared with vehicle-treated controls (-28.7±2.0 g)
(P<.01, unpaired Student's t test) (Fig 6B).
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Separate experiments to determine the effect of CP-0597 on MABP and
core body temperature after MCAO demonstrated that CP-0597 treatment
had no effect on either parameter either during
arterial occlusion or for 2 hours after reperfusion (Fig 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study evaluated the effect of the selective bradykinin B2 receptor antagonist CP-0597 on ischemic brain injury induced by rMCAO in the rat. Treatment with CP-0597 significantly reduced brain swelling, infarct size, and neuronal necrosis and improved behavioral outcome and body weight loss without affecting MABP or core body temperature. These results support a role for bradykinin in the pathogenesis of ischemic brain injury and provide a strong rationale for the use of B2 receptor antagonists as therapeutics for the treatment of stroke.
The aim of the present experiments was to determine the efficacy of CP-0597 as a potential treatment for stroke. Previous work differentiated the roles of B1 and B2 receptors after permanent focal cerebral ischemia in the rat, demonstrating that blockade of B2 receptors is protective, while antagonism of B1 receptors alone or in combination with B2 receptor blockade is detrimental to neuronal recovery and survival.21 26 These studies demonstrated the significant dose-dependent neuroprotective effect of treatment with CP-0597 and led to the design and choice of dosing regimen used in the present experiments. The dose used—300 ng/kg per minute infused over 24 hours—was the most effective at reducing infarct volume after permanent MCAO21 ; however, further studies are required to determine the most effective dose of this compound after rMCAO. Separate studies reported elsewhere determined that the time from osmotic pump implantation to reach pharmacologically active levels of CP-0597 in the circulation was between 20 and 30 minutes,21 suggesting that this compound can provide significant benefit at this dose when administered a considerable time after the initiation of the pathological changes that culminate in brain damage. In our study, since CP-0597 was administered after arterial occlusion, biologically active levels of the compound were not present in the circulation at the time the tissue was compromised, yet marked inhibition of neurodegeneration and edema was observed. This finding strengthens the relevance of the results to the treatment of the disease state. It has been suggested that histological assessments of neurodegeneration and edema are ultimately the most predictive measurements of potential therapeutic value of a compound27 ; however, the demonstration that CP-0597 can also promote functional recovery after rMCAO adds weight to the overall efficacy profile of this antagonist. Indeed, the level of protection offered by CP-0597 against ischemia/reperfusion–induced cerebral infarction, edema, and behavioral changes is markedly greater than that observed after treatment with other neuroprotective agents such as the glutamate antagonists MK80128 and NBQX29 in comparable rat models of rMCAO.
Modulation of physiological parameters has been shown to significantly alter the degree of ischemic damage, particularly in models of transient focal cerebral ischemia.30 31 We demonstrated that despite the vasoactive5 and pyrogenic properties32 of bradykinin, the effects of CP-0597 cannot be attributed to modulation of MABP or core body temperature after rMCAO. However, further studies are required to evaluate the effect of CP-0597 on local brain temperature to conclusively determine that this compound is not acting through an intracerebral hypothermic action.
The mechanism by which endogenous bradykinin mediates ischemic brain injury remains unclear, but numerous possibilities exist. Bradykinin activates all the mechanisms responsible for the early manifestations of inflammation, including arteriolar dilatation, increased vascular permeability, and consequent vasogenic edema formation.17 18 Such responses to exogenous33 or endogenous34 bradykinin exposure have been attributed to prostaglandin production, free radical generation, and lipid peroxidation,2 which are cardinal features of cerebral ischemic pathology.35 Bradykinin is also a potent stimulator of other inflammatory mediators such as cytokines15 and acts as a leukocyte chemoattractant.36 Pertinent to the neuronal dysfunction that occurs after an ischemic insult to the brain, bradykinin can also stimulate nitric oxide and free radical production and glutamate release and elevate neuronal intracellular calcium levels.1 14 16 37 The diverse sequelae resulting from bradykinin receptor activation together with the identification of tissue kallikrein and bradykinin receptors throughout the brain4 10 11 12 indicate that it is likely that the beneficial effects observed after treatment with CP-0597 are due to inhibition of several detrimental pathological actions of bradykinin after cerebral ischemia.
Since all the components of the kallikrein-kinin system are present in both the brain and the blood,1 the detrimental effects of bradykinin may occur either in the brain parenchyma and/or on the cerebral vasculature. Functional studies have shown that bradykinin can act on astrocytes,16 neurons, and the cerebral vasculature.1 2 18 Localization studies have identified B1 and B2 receptors on brain neurons,12 on the luminal and abluminal surfaces of endothelial cells, and on smooth muscle of both cerebral arterioles and postcapillary venules.18 Future studies are planned to determine the site of action of CP-0597 in the brain after cerebral ischemia and may shed some light on the site of action of bradykinin in the brain and the mechanism(s) responsible for the protective effect of CP-0597.
The demonstration that bradykinin is involved in the pathogenesis of ischemic brain injury is consistent with the emerging view that cerebral ischemia/stroke is a disease characterized by an inflammatory response rather than simply acute neurodegeneration. Numerous avenues of research are being investigated to discover viable therapeutic agents for the treatment of stroke patients,38 and more recently inhibitors of inflammatory mediators such as cytokine antagonists and anti–adhesion molecule therapies are proving efficacious in preclinical studies.39 40 41 The search for effective pharmacological agents for the treatment of stroke has been plagued by the complex nature of the pathology of this disease and the toxicity issues surrounding compounds that directly modify neuronal function.38 Clearly, the solution to these problems must be either a multifaceted approach that attenuates several processes in the ischemic cascade and/or inhibition of one of the early mediators. Bradykinin may be one such mediator, and the marked protective effect of CP-0597 against ischemia-induced neurodegeneration and cerebral edema indicates that antagonism of the actions of bradykinin at the B2 receptor may have significant therapeutic potential in the treatment of stroke.
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Selected Abbreviations and Acronyms |
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Received January 14, 1997; revision received March 28, 1997; accepted April 2, 1997.
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References |
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