(Stroke. 1995;26:2177-2183.)
© 1995 American Heart Association, Inc.
Articles |
Failure of Isradipine to Reduce Infarct Size in Mouse, Gerbil, and Rat Models of Cerebral Ischemia
From the Departments of Neurology Research (S.J.B., N.I.W., N.A.S., A.L.R., P.D.K., T.C.H., A.J.H.) and Biophysical Sciences (J.C.R., D.C.H.), SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Correspondence to Sarah J. Bailey, Department of Neurology Research, SmithKline Beecham, New Frontiers Science Park, Third Ave, Harlow, Essex, CM19 5AW, UK. E-mail sarah_j_bailey%notes@sb.com.
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Abstract |
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Background and Purpose The dihydropyridine L-type calcium channel blocker isradipine has been reported to exhibit neuroprotective properties in some, but not all, studies performed in the rat middle cerebral artery occlusion (MCAO) model. In the present study, we examined isradipine in several other models of focal and global ischemia: rat rose bengal, mouse MCAO, and gerbil bilateral carotid artery occlusion (BCAO). For comparison, a novel calcium channel blocker, SB201823A, that we have previously shown to be neuroprotective in rat and gerbil models was also examined in the mouse.
Methods In the gerbil BCAO model, isradipine was administered at 2.5 mg/kg IP as a single dose 60 minutes after ischemia (n=10). Corresponding controls received vehicle (n=10), and sham-operated animals received no treatment (n=6). Locomotor activity and histological assessments were made at 4 days after ischemia. In the rat photothrombotic occlusion model, isradipine was administered at 2.5 mg/kg IP as a single dose 60 minutes after ischemia (n=10), and corresponding controls (n=10) received vehicle. Histological assessment was made at 7 days after ischemia. In the mouse MCAO model, isradipine was also administered at 2.5 mg/kg IP as a single dose 60 minutes after ischemia. Histological assessments were made at 1 (n=13), 2 (n=9), and 4 (n=9) days after ischemia. Vehicle numbers were n=10, n=6, and n=8, respectively. Isradipine and SB201823A were also examined using a combined preischemia and postischemia regimen. Isradipine was administered at 2.5 mg/kg IP before occlusion, 1.25 mg/kg IP 1 hour after occlusion, 1.25 mg/kg IP 2 hours after occlusion, and 2.5 mg/kg twice a day for 3 days after occlusion (n=16). Corresponding controls received vehicle at the same time points (n=14). SB201823A was administered 30 minutes before occlusion, 30 minutes after occlusion, and twice daily for 3 days (n=12). Corresponding controls received vehicle (n=9). Histological assessment was performed at 4 days after ischemia.
Results When given after ischemia, isradipine failed to affect lesion volume in both the rat and mouse models. In the gerbil, locomotor hyperactivity and hippocampal cell loss were unaffected. Given before and after ischemia in the mouse, isradipine was also ineffective, whereas SB201823A produced a significant reduction in lesion volume.
Conclusions The L-type calcium channel blocker isradipine was devoid of neuroprotective activity in focal and global models of cerebral ischemia in three species of normotensive animals. These results were compared with data for the novel calcium channel blocker SB201823A, which exhibited a significant effect after pre- and postocclusion administration in the mouse model of permanent focal ischemia.
Key Words: calcium channel blockers • cerebral ischemia • neuroprotection • gerbils • mice • rats
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Introduction |
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Preclinical studies of L-type calcium channel antagonists such as nimodipine have produced equivocal results in models of cerebral ischemia.1 For example, in the rat MCAO model of focal ischemia, neuroprotection has been observed with nimodipine in some,2 3 but not all, studies.4 The mechanism by which such compounds produce a neuroprotective effect is unresolved, although it has been suggested that dihydropyridines act preferentially on cerebral blood vessels to restore tissue perfusion at the infarct periphery.5 6 However, calcium influx plays a major role in mediating cell death observed in ischemia; therefore, the reduction in calcium influx caused by blockade of voltage-gated calcium channels may also be an important factor influencing the neuroprotective effects of these compounds.7 Nifedipine and isradipine block the toxicity induced by the glutamate agonist
-amino-3-hydroxy-5-methyl-5-isoxazoloproprionate (AMPA) in
cultured cerebellar granule cells.8 Isradipine has also
been reported to reduce infarct size in rat MCAO models when given
either before and after ischemia or after ischemia
only.6 9 In a separate study, isradipine administered
before and after ischemia failed to reduce infarct
size,5 although this study was subsequently criticized on
methodological grounds.10 The present series of studies extends investigation of the putative neuroprotective actions of isradipine to three other models of cerebral ischemia. We have previously shown that a novel type of calcium channel antagonist, SB201823A, which acts preferentially at calcium channels other than the L-type, has neuroprotective properties when given after ischemia in both global (BCAO in the gerbil) and focal (photothrombotic lesions in the rat) stroke models.11 Recently, this activity has been confirmed after postischemia dosing in both rat and mouse MCAO models.12 In the present study, we examined the effects of isradipine in the gerbil BCAO and rat photothrombotic models of stroke. In addition, the effects of isradipine and SB201823A were compared in the mouse MCAO model.
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Materials and Methods |
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Surgery
All procedures were reviewed by a SmithKline Beecham internal ethics committee. The animals were maintained on a 12-hour light/dark cycle and allowed access to food and water ad libitum.
Gerbil BCAO
Adult male Mongolian gerbils (Meriones unguiculatus)
weighing 60 to 100 g (B&K Universal Ltd) were anesthetized with
6% halothane in 100% O2 and maintained at 3% halothane.
In operated animals, both carotid arteries in the neck were exposed and
occluded for 10 minutes with atraumatic aneurysm clips, during
which time the wound site was irrigated with sterile sodium chloride
solution to prevent tissue dehydration. A visual check was made to
ensure that the flow through the vessels had ceased. Flow was
reestablished on removal of the clips. Sham operations were carried out
as above but without occluding the arteries. Throughout the surgical
procedure, body temperature was maintained at 37±1°C with a heated
blanket with feedback control. The animals were maintained in an
incubator at 37°C until they regained consciousness. After surgery,
animals were individually housed and allowed free access to food and
water. Body weight was monitored daily.
Four days after induction of ischemia, the animals were exposed to a simple behavioral test to assess their ability to habituate to a novel open-field environment. BCAO in the gerbil causes a locomotor hyperactivity,13 14 which was measured by an activity-monitoring system consisting of clear acrylic boxes, each with three banks of photoemitters and detectors (ACE Software Ltd). Gerbils were placed individually in the boxes, and locomotor activity was measured by recording the number of beam breaks (counts) over a 60-minute period. Statistical assessment was carried out using an in-house program that combined ANOVA with a check for the influence of testing box and time of test.
Immediately after the behavioral studies, the animals were killed with an overdose of sodium pentobarbital and perfusion-fixed with NBF containing 5% sucrose. The brains were removed and placed in NBF for a minimum of 24 hours before sectioning and staining. A total of 12 serial coronal sections (12 µm thick) were cut through the dorsal hippocampus and stained with 1% cresyl fast violet. Viable cell area in the CA1 to CA3 region of the hippocampus was measured densitometrically using a Quantimet 920 image analyzer (Cambridge Instruments).11 This assessment was made blind. Data were analyzed by one-way ANOVA.
Rat Photothrombotic Lesions
To induce photothrombotic lesions,15 16 17 18 19 20 21 22 male Lister
hooded rats (Charles River) weighing 250 to 280 g were
anesthetized with 5% halothane in 95%
O2/5% CO2 and subsequently maintained
at 3% halothane. The animals were placed in a stereotaxic
frame, and anesthesia was maintained with a
purpose-built face mask (designed and built in-house). A
midline incision was made in the scalp between the eyes and ears, and
the pericranium was displaced to provide a clear skull surface. A
bifurcated fiber-optic light guide (3.0 mm in diameter) from a 300-W
xenon arc lamp (Oriel Scientific Ltd) was positioned on the skull at
the bregma in a holder designed to center the heads of the light guide
2.5 mm to either side of the midline. Rose bengal dye (20 mg/kg;
Aldrich) was injected into a lateral tail vein, and the skull was
illuminated for 5 minutes. The scalp was sutured, and the animals were
then returned to their home cages to recover. Throughout the procedure,
body temperature was maintained at 37±1°C with a heated blanket with
feedback control. Sham operations were carried out as above, with the
rats receiving rose bengal dye but no illumination.
After recovery, body weight was monitored daily. Seven days after surgery, the animals were killed with an overdose of sodium pentobarbital and perfusion-fixed with NBF containing 5% sucrose. The brains were stored in NBF for a minimum of 24 hours before sectioning and staining. Coronal sections (60 µm) were cut through the length of the lesion and stained with cresyl fast violet. Infarct volume was calculated by first measuring the area of the lesion on successive sections using a Quantimet 920 image analyzing system (Cambridge Instruments) and then computed using Simpson's rule. Data were assessed by three-way ANOVA and Student's t test.
Mouse MCAO
Adult male CD1 mice (Charles River) in the weight range of 25 to
30 g were anesthetized with 250 mg/kg tribromoethanol injected
intraperitoneally. Focal cerebral
ischemia23 24 25 was induced as follows: A temporal
approach was adopted to occlude the right MCA. With the aid of an
operating stereomicroscope (M3Z Wild, Leica UK Ltd), an incision
was made between the outer canthus of the eye and the external
auditory meatus. The temporalis muscle was bisected and retracted to
expose the temporolateral surface of the skull. The MCA was exposed by
means of a burr-hole craniotomy, performed with a
dental drill. A thin layer of bone was preserved to protect the dura
mater and cortex surface from mechanical damage and thermal injury.
Remaining bone was removed with watchmaker's forceps and a
fine-gauge needle. At this stage, the artery was examined closely
under x40 magnification to reveal both the major and minor branches of
the MCA within the limits of the cranial window. The dura immediately
overlying the MCA was cut with fine-gauge needles and removed. The
MCA was occluded distal to the branch point by microbipolar diathermy
and then severed using fine-gauge needles. The temporalis muscle
and then the skin incision were sutured using 6/0 polyglactin sutures
(Ethicon UK, Ltd).
Throughout the procedure, body temperature was maintained within the normal limits (37±1°C) with a heating blanket with feedback control. After the surgical procedure, mice were maintained in an environmental temperature of 37°C for 120 minutes, during which time they recovered from the anesthetic and were then returned to normal housing conditions.
After recovery, body weight was monitored daily. Up to 4 days after ischemia, mice were killed with a lethal dose of sodium pentobarbital, and their brains were removed and stored in NBF. Preliminary studies (S.J. Bailey, S.R. Patel, unpublished data, 1992) have revealed that lesions were mature by day 4 after occlusion and edema was minimal; therefore, in subsequent experiments this was selected as the end point unless otherwise stated. The branching pattern of the MCA was again recorded, and animals (<10%) displaying atypical branching (ie, additional branch points distal to the point of occlusion and not visible in the cranial window) were rejected. Inclusion of these brains would have introduced unnecessary variation into the quantitative measurement of ischemia.26 27 Brains were fixed for a minimum of 48 hours before processing for histological examination. Coronal sections (60 µm) were taken and stained with cresyl fast violet. Infarct volume was determined as with the rose bengal model. Data were analyzed using one-way ANOVA, and statistical significance was defined as P<.05.
Anesthetized Rat Cardiovascular
Monitoring
Male Hooded Lister rats (Charles River) weighing 276 to 400 g
were anesthetized using halothane (4.5% induction, 2%
maintenance, in 2 l per minute O2). The femoral
vein and artery were cannulated (2- or 3-fg cannulas, Portex Ltd), and
rats were allowed to respire spontaneously. BP was recorded with a
Druck BP transducer (PDCR 75) and Macintosh IIci hardware. HR was
derived from the arterial pulse with MacLab/8 software. BP
and HR recordings were taken continuously for a minimum of 10
minutes before administration of the compound. Diastolic BP
(millimeters of mercury) and HR (beats per minute) were recorded
every 5 minutes for 30 minutes, beginning immediately before drug
administration (time 0), and calculated as the percentage change from
time 0. The percentage change at 30 minutes was used to compare drug
effects. Animals were then killed with an overdose of anesthetic.
Drug Treatment
Ischemia Studies
Isradipine (PN 200-110, RBI) was dissolved in 19% ethanol and
19% PEG in 0.9% sodium chloride solution. SB201823A
(4-[2-(3,4-dichlorophenoxy)ethyl]-1-pentylpiperidine hydrochloride)
was dissolved in 10% hydroxypropyl-ß-cyclodextrin (Janssen
Biotech NV) in 0.9% sodium chloride solution. In all experiments, a
control group of animals received the appropriate vehicle. All drugs
were administered via the intraperitoneal route in
a dosing volume of 4 mL/kg.
Gerbil BCAO and rat rose bengal models. Isradipine was administered as a single dose of 2.5 mg/kg IP given 60 minutes after ischemia. Group sizes in the rat model were 10 in both drug- and vehicle-treated groups; in the gerbil model, 6 in the sham vehicle-treated group, 13 in the ischemic vehicle-treated group, and 12 in the ischemic isradipine-treated group.
Mouse MCAO. Three separate experiments were carried out. In experiment 1, isradipine was administered after occlusion only, as a single dose of 2.5 mg/kg given 60 minutes after occlusion. Brains were removed for analysis at a range of postocclusion time points: 24 hours (n=13), 48 hours (n=9), or 96 hours (n=9). Numbers of animals receiving vehicle were n=10, n=6, and n=8, respectively. In experiment 2, isradipine was administered at 2.5 mg/kg 1 hour before occlusion followed by 1.25 mg/kg at 1 and 2 hours after occlusion, and at 2.5 mg/kg twice daily for 3 days after occlusion (n=16; n=14 in the vehicle-treated group). Brains were removed on day 4. Animals that died shortly after administration of isradipine (ie, within 1 hour) were excluded and replaced directly with additional animals with the same treatment. In experiment 3, SB201823A was administered at 10 mg/kg 30 minutes before occlusion, 30 minutes after occlusion, and twice daily for 3 days after occlusion (n=12; n=9 in the vehicle-treated group). Brains were removed for analysis 4 days after occlusion.
Cardiovascular Monitoring
Isradipine was dissolved in 19% PEG with 19% ethanol in 0.9%
sodium chloride solution; SB201823A was prepared in 10%
hydroxypropyl-ß-cyclodextrin in 0.9% sodium chloride solution.
Control animals received vehicle alone (4 mL/kg IP bolus). Isradipine
(2.5 mg/kg) and SB201823A (10 mg/kg) were given
intraperitoneally.
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Results |
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Gerbil BCAO Model
Fig 1
shows that isradipine (2.5 mg/kg IP 60
minutes after occlusion) had no effect on the locomotor hyperactivity
caused by BCAO. There was no significant difference observed between
locomotor activity in the vehicle- and isradipine-treated groups
(P=.96). Locomotor activity in the ischemic control
group was significantly higher (P=.004) than in the sham
control group. Similarly, Fig 2 shows that isradipine
failed to protect cells from ischemia-induced death in the
CA1 to CA3 regions of the dorsal hippocampus. There was no significant
difference (P=.99) in viable cell area between the vehicle-
and isradipine-treated groups. Viable cell area was significantly
less (P=3.3x10-6) in
the ischemic group than in sham-operated controls.
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Rat Rose Bengal Model
Isradipine given as a single dose of 2.5 mg/kg IP 60 minutes after
ischemia did not have a significant effect (P=.27)
on lesion volume when compared with the ischemic control group
(Fig 3).
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Mouse MCAO Model
Fig 4 shows the effects of a single dose (2.5 mg/kg
IP) of isradipine given 1 hour after occlusion on lesion volume at
various postischemia time points (24, 48, and 96 hours). At
all time points, isradipine failed to produce a significant reduction
in lesion volume compared with time-matched vehicle-treated
control animals. In both the drug- and vehicle-treated groups,
lesion volume showed a significant reduction (P=.006 and
P=.001, respectively) from 24 to 96 hours after occlusion.
This may be attributed to regression of edema in the cortex and the
accompanying cellular changes.28 29 A 12% to 15%
mortality was observed in the isradipine-treated groups compared
with 0% in corresponding controls. These mortalities were observed
shortly after (ie, within 1 hour) administration of isradipine.
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The effect of isradipine on lesion volume at day 4 following a
preocclusion and postocclusion dosing regimen is shown in Fig 5a. Again, isradipine failed to produce a significant
reduction in lesion volume compared with vehicle-treated controls.
By comparison, animals treated with SB201823A, after a similar
preocclusion and postocclusion dosing regimen, demonstrated a
significant reduction (P=.02) in lesion volume compared with
controls at 4 days after ischemia (Fig 5b).
Similarly, a 12% mortality was observed in the isradipine-treated
group compared with 0% in corresponding controls. Again, mortalities
were observed within 1 hour of administration of the first dose of
isradipine.
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Anesthetized Rat Cardiovascular
Monitoring
In halothane-anesthetized rats, the changes in
diastolic BP and HR over the 30-minute period following
administration of isradipine (2.5 mg/kg IP) were similar in magnitude
to those recorded in the vehicle control group
(Table). Thus, isradipine had little or no
cardiovascular effects in this test.
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SB201823A (10 mg/kg IP) produced a modest fall in diastolic BP compared with that in the corresponding vehicle-treated group. HR was unaltered in the drug-treated group but fell by 11% in the control group. Therefore, SB201823A evoked minor changes overall in these parameters in this model.
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Discussion |
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The dihydropyridine L-type calcium channel antagonist isradipine has been reported to be neuroprotective in the MCAO model in SHR after a variety of preocclusion and postocclusion dosing regimens.3 6 30 31 32 33 However, other studies in normotensive rats5 34 have failed to demonstrate a significant neuroprotective effect of this drug in experimental focal and global ischemia. In the present study, isradipine when given after ischemia did not exhibit neuroprotective potential in three models of ischemia. With similar protocols, the novel calcium antagonist SB201823A reduced ischemia-induced lesions in the same gerbil and rat11 models, as well as in a mouse12 model. Unlike SB201823A, isradipine also failed to reduce the hyperlocomotor activity induced by temporary BCAO in gerbils.
Experimental work with calcium channel antagonists conducted in various animal models of cerebral ischemia has produced confounding results, probably as a result of the intrinsic variability of these models. Variations in experimental conditions (such as anesthesia, species, time, dose, route of administration, and duration of drug administration) make definitive conclusions virtually impossible. For example, nimodipine given after ischemia significantly reduced infarct size at 4 days after occlusion in the gerbil BCAO model,35 but in the same model, when given before and after ischemia, it was not neuroprotective. Even drugs of the same class have produced divergent results.1
Our investigation of isradipine in the rat photothrombotic model appears to be the first report of the effects of a dihydropyridine drug in this focal model, although other calcium channel antagonists, such as the diphenylalkamine flunarizine, produced a reduction in infarct size and reversal of some motor deficits.1 In contrast, in the present study, isradipine failed to reduce even lesion volume. Isradipine also failed to reduce lesion volume in the mouse MCAO model and CA1-CA3 damage in the gerbil BCAO model. Isradipine has, however, been reported to induce a substantial reduction in comparative infarct size in SHR.5 6 This occurred whether the drug was administered before, before and after, or after occlusion only3 31 and may be attributed in part to its hypotensive effects. In the same model, and following an intensive presurgery and postsurgery dosing regimen, isradipine reduced both hyperlocomotion and CA1 cell death.36 In contrast, Ohta et al34 found no effect with isradipine at 5 mg/kg in a rat model of BCAO plus hypotension. As confirmed by the present study, isradipine has demonstrated an inability to significantly reduce ischemic damage in normotensive models.
The neuroprotective efficacy of SB201823A has now been shown in the mouse MCAO model after a preocclusion and postocclusion dosing regimen. However, with a similar dose schedule, isradipine was ineffective. It seems unlikely that the differences observed in the activity profiles of these two calcium channel antagonists in ischemia models may be attributable to the extent of their cardiovascular effects, since both drugs produced little or no change in diastolic BP or HR in halothane-anesthetized rats. These experiments were performed using doses of both drugs that were the same as those given as the first dose in the ischemia models. For the latter, both the rats and gerbils were fully recovered from anesthesia when they were dosed, whereas the mice were not. The mortalities in mice after isradipine may be due to the combination of the presence of anesthetic (tribromoethanol) and an isradipine-induced hypotensive response.
Another possible explanation for the lack of a neuroprotective effect of isradipine in the present study is that isradipine was administered 60 minutes before or after ischemia. Sauter and Rudin30 reported that isradipine was rapidly metabolized with a plasma half-life of 1 hour; therefore, there may not have been sufficient active drug present to exert a neuroprotective effect. However, Barone and coworkers (White et al,37 1994) reported that isradipine administered subcutaneously 60 minutes after MCAO produced a reduction (P<.05) in infarction in SHR.37 The use of this route may have led to slower absorption of the drug into the circulation and less extensive first-pass metabolism than arose from the intraperitoneal route used in our studies. The effects of isradipine were determined at 24 hours after occlusion in the mouse MCAO model only, but at much later time points in the gerbil, rat, and also the mouse. We chose longer time points to allow for a reduction in edema to occur, thus giving a clearer idea of the extent of true long-term neuroprotection. Interestingly, isradipine has been reported to produce a reduction in infarct size at 24 hours with MRI methods, but the effect was apparently reduced when histological assessment was made 5 days after MCAO.30 Despite its known diuretic properties,38 isradipine had no apparent effect on cerebral edema as judged by its failure to reduce lesion volume at 24 hours compared with vehicle. Others have shown that isradipine given intravenously at the time of MCAO or reperfusion reduced cerebral edema and calcium accumulation in Wistar rats,9 whereas in Fisher 344 rats isradipine (0.24 mg/kg IV given 20 minutes before MCAO) had no histological effect on lesion volume at 24 hours.5 In another study, subcutaneous isradipine (2.5 or 5 mg/kg) failed to reduce ischemia in Wistar rats produced by 15 minutes of BCAO or 30-minute hypoglycemia when assessed at 7 days after the insult.34 This further supports the hypothesis that reductions in lesion volume caused by isradipine are seen only in hypertensive animals.
One possible explanation for the difference between the results reported here and those of Sauter and Rudin30 is that lesion volumes were calculated differently. Sauter and Rudin calculated lesion volumes by counting the numbers of voxels from a nuclear MR image or reported a neuroprotective effect by presenting the mean drug-treated lesion volume from images as a percentage of the mean vehicle-treated lesion volume. By adopting the latter method in the present study, isradipine would have produced a 20% reduction in lesion volume in the rat photothrombotic model and reductions ranging from 14% to 18% in the mouse MCAO experiments. The MRI protocol used detected intracellular water, and thus the lesion was defined as an area of edema rather than terminally compromised cells. Also, histological data were not presented at corresponding time points. Sauter et al31 reported that a single dose of isradipine (2.5 mg/kg) after MCAO produced a 50% to 60% reduction in both lesion volume (as measured by MRI at 24 hours) and brain wet weight. Such a result might be expected if the mode of action of isradipine was antiedemic rather than neuroprotective. Abe et al9 stated that isradipine prevented edema formation by inhibiting the accumulation of calcium, and it has been demonstrated in humans that isradipine has diuretic properties.38 In the present study, the absence of a neuroprotective effect in the mouse MCAO model, when examined by histology 24 hours after occlusion, lends support to the theory that at this point any reduction in lesion volume is due to effects on edema rather than cytoprotection.
In summary, we have been unable to demonstrate chronic neuroprotection with isradipine in three models of normotensive ischemia with dosing regimens similar to those previously reported to be efficacious in the MCAO model in SHR. In contrast, SB201823A exhibited neuroprotective activity. A number of factors, either singly or in combination, may have contributed to the absence of demonstrable neuroprotective activity with isradipine in our models. These factors include the normotensive nature of our models (as also reported by others in rats5 34 ), the use of the intraperitoneal route leading to inadequate exposure of tissues to drug, and the profile of isradipine as an L-type calcium channel blocker, thus being less than optimal for producing neuroprotection.
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Received January 31, 1995; revision received May 31, 1995; accepted July 28, 1995.
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