(Stroke. 1995;26:466-472.)
© 1995 American Heart Association, Inc.
Articles |
Neuroprotective Properties of the Novel Antiepileptic Lamotrigine in a Gerbil Model of Global Cerebral Ischemia
From the Division of Pharmacology, Burroughs Wellcome Co, Research Triangle Park, NC 27709.
Correspondence to Barrett R. Cooper, PhD, Division of Pharmacology, Burroughs Wellcome Co, 3030 Cornwallis Rd, Research Triangle Park, NC 27709.
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Background and Purpose Elevated glutamate levels are thought to be a primary cause of neuronal death after global cerebral ischemia. The purpose of this study was to investigate the potential neuroprotective effects of lamotrigine, a novel antiepileptic drug that inhibits the release of glutamate in vitro, with both behavioral and histological measures of global ischemia in gerbils.
Methods The common carotid arteries of gerbils were occluded for either 5, 10, or 15 minutes. Twenty-one days after reperfusion, gerbils were tested for impairments in a spatial memory task (Morris water maze). After water maze testing the animals were killed, and damage to hippocampal pyramidal cells was assessed. The effect of lamotrigine on the behavioral and histological outcome of either 5 or 15 minutes of global ischemia was evaluated.
Results Bilateral occlusion of the common carotid arteries for 5 minutes resulted in severe degeneration of hippocampal CA1 and CA2 pyramidal cells. Lamotrigine significantly prevented loss of hippocampal CA1 neurons when administered acutely (100 mg/kg PO) immediately after reperfusion or when administered in two equal doses of 30 or 50 mg/kg 2 hours before and immediately after reperfusion. Gerbils subjected to 5 minutes of ischemic insult were not impaired in their ability to solve a spatial memory task 21 days after cerebral ischemia. However, gerbils subjected to 10 and 15 minutes of carotid artery occlusion showed significant impairment in their ability to solve a water maze task. Lamotrigine significantly protected against the cognitive deficits associated with 15 minutes of cerebral ischemia. Histologically, increased durations of cerebral ischemia resulted in a progressive loss of CA1, CA2, and CA3 pyramidal cells. Lamotrigine completely protected gerbils exposed to 15 minutes of cerebral ischemia against CA3 cell loss and greatly reduced damage to the CA1 and CA2 cell tracts of the hippocampus. Lamotrigine also reduced the mortality associated with 15 minutes of ischemia.
Conclusions Lamotrigine had neuroprotective effects in a gerbil model of global cerebral ischemia. Lamotrigine protected gerbils against behavioral deficits resulting from 15 minutes of carotid occlusion and also prevented histological damage resulting from 5 and 15 minutes of global cerebral ischemia.
Key Words: behavior, animal • cerebral ischemia • neuroprotection • gerbils
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Introduction |
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Surgical procedures that involve the reduction or interruption of blood supply to the brain as well as events such as stroke, cardiac arrest, and traumatic brain injury are often accompanied by memory loss and other neuropsychiatric signs that persist for several months during recovery.1 2 3 4 5 6 These changes are thought to be related to global cerebral ischemia. In animals, 5-minute or longer periods of global cerebral ischemia result in cell death, especially in the hippocampus.7 8 9 The development of mazes to study spatial learning and memory has provided a way to study the protective effects of drugs on both the behavioral consequences and the neurological damage to the hippocampus and other areas involved in the neurotoxic effects of ischemia.
Glutamate has been the focus of recent investigations into the neurochemical events leading to neuronal cell death in cerebral ischemia. During cerebral ischemia, synaptic glutamate release coupled with the failure of uptake systems leads to large increases of extracellular glutamate.10 11 12 Elevated glutamate levels are thought to be a primary cause of neuronal death after ischemia.13 14 15 Studies that support this theory demonstrate that N-methyl-D-aspartate antagonists have neuroprotective properties in animal models of ischemia.16 17 18 19 20
Lamotrigine [3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine] is a novel antiepileptic drug that inhibits use-dependent sodium ion channels and reduces the synaptic release of glutamate in vitro.21 22 23 Recent studies24 25 indicate that lamotrigine and its analogue 1003C87 reduce infarct size after middle cerebral artery occlusion in the rat. The postulated role of glutamate release in the neurotoxic effects of ischemia led us to investigate the potential neuroprotective properties of lamotrigine in gerbils using behavioral and histological measures of global ischemic damage.
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Materials and Methods |
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Materials
Male Mongolian gerbils (Tumblebrook Farm, West Brookfield, Mass) weighing 60 to 70 g were used for these studies. Gerbils were housed four per cage and were maintained on a 12-h/12-h light/dark cycle (lights on at 6 AM) at a temperature of 21°C throughout the study. Food and water were available ad libitum. The procedures used in these studies were conducted in accordance with the US Health Service, National Institutes of Health guidelines for the care and use of laboratory animals.
Surgical Procedures
Cerebral ischemia was induced by the method of Ito et
al7 as modified by Carroll and Beek.26
Gerbils were anesthetized with a mixture of halothane gas (3%) and
room air. An incision was made along the midline in the ventral neck,
and both common carotid arteries were occluded for either 5, 10, or 15
minutes by means of microaneurysm clips. After clip removal, the
incision was closed and the anesthesia discontinued. Body temperature
was maintained throughout the surgery. Animals used in behavioral
studies were allowed to recover for at least 3 weeks before testing
began. Sham-operated animals received the same surgical procedure
except that the carotid arteries were not occluded.
Drug Administration
Lamotrigine (Lamictal; Burroughs Wellcome Co) was suspended in a
0.5% methyl cellulose solution and administered orally in a volume of
0.01 mL/g body wt. For behavioral studies, two doses of lamotrigine (50
mg/kg) or vehicle were administered. The first dose was given 2 hours
before ischemia, and the second was administered immediately after
reperfusion.
Plasma and Brain Determinations
Gerbils were anesthetized with CO2 before the
collection of blood in evacuated tubes (15% ethylenediaminetetraacetic
acid) via cardiac puncture. The blood was centrifuged at
2900g for 5 minutes to obtain plasma. Plasma levels of
lamotrigine were determined by reversed-phase high-performance liquid
chromatography with UV detection at 210 nm. One-milliliter aliquots of
plasma were made basic to pH 10.0 by the addition of 10 µL 10N NaOH
before extracting twice with 3 mL methyl-t-butyl ether
(MTBE). The combined organic phases were dried under nitrogen. The
samples were reconstituted to 100 µL in a mobile phase and applied to
a 15-cmx4.6-mm C-18 base deactivated column. Lamotrigine was eluted
with the use of a mobile phase consisting of 20 mmol/L glacial acetic
acid and 20 mmol/L triethylamine containing 20% CH3CN.
For brain determinations, gerbils were anesthetized with CO2 before decapitation. The whole brain was weighed and then homogenized in 4 mL of carbonate buffer (0.6 mol/L, pH 9.5). One milliliter of this homogenate was extracted by mixing it with a total of 6 mL (2x3 mL) of 1.5% isoamyl alcohol in n-heptane. The organic layer was transferred into tubes containing 1 mL of 0.1N HCl. After mixing and centrifuging to separate phases (2900g for 2 minutes), the isoamyl alcohol layer was discarded. One half milliliter of carbonate buffer and two drops of 1N NaOH were added to the HCl layer, which was extracted with a total of 6 mL (2x3 mL) of MTBE. The final organic phase was dried in tubes containing 10 µL of 0.1N HCl with the use of a Speed Vac Sample Concentrator. Samples were reconstituted, and lamotrigine concentrations were determined by the methods described above for plasma.
Histological Procedures
Animals were killed 4 days after surgery except for gerbils used
in behavioral studies, which were killed after water maze testing.
Gerbils were decapitated under halothane anesthesia, and their brains
were removed and fixed for at least 3 days in 10% buffered formalin.
The brains were processed for paraffin sectioning, and a 10-µm
coronal section of the anterior hippocampus was obtained. The sections
were stained with cresyl violet and microscopically evaluated for
hippocampal damage. Damage to CA1 and CA3 cells was quantified by
counting the viable cells in four 0.4-mm lengths (two samples from each
hemisphere) of each respective pyramidal cell tract of the hippocampus.
CA2 cell damage was assessed in a similar manner, except that cells
were counted in two 0.4-mm lengths of the CA2 cell tract.
Behavioral Testing
Training in a modified Morris water maze27 was
carried out 3 weeks after cerebral ischemia. The apparatus consisted of
a circular galvanized steel tank 79 cm in diameter and 58 cm high,
which was filled with water (27°C) to a depth of 13 cm. (The water
depth on the first day of training was 6 cm to allow the animals to
acclimate to the test conditions.) Powdered milk was added to the water
to make it opaque. Three different visual cues were placed around the
inside wall of the tank at a level that would be visible to the
gerbils. A circular platform 7 cm in diameter remained in a fixed
location 20 cm from the apparatus wall and was 1 cm below the surface
of the water.
Each animal was given three daily trials with a 5-minute intertrial interval for 9 days. Each gerbil was individually placed in the apparatus at one of three preselected locations and allowed 1 minute to escape to the hidden platform. Animals not finding the platform after 1 minute were guided to it by the experimenter. Animals were allowed to remain on the platform for 15 seconds and were then returned to their holding cage until the next trial. After 9 days of testing in the Morris water maze the animals were killed and their brains examined for hippocampal damage.
Statistical Analysis
All histological data were analyzed with a one-way ANOVA.
Behavioral data were analyzed with a two-way ANOVA (treatmentxtrial).
Post hoc comparisons between independent groups were made with the
Tukey test. Animal mortality data were analyzed with a
2 test. In all cases, the acceptable level for
statistical significance was P<.05.
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Results |
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Effects of Different Durations of Occlusion on Water Maze Performance
Fig 1
shows a direct correlation between
performance in the Morris water maze and duration of cerebral ischemia.
While there were no significant differences in performance of gerbils
after 5 minutes of occlusion when compared with control, 10 and 15
minutes of occlusion resulted in significant impairments in acquisition
of the spatial task (ANOVA: F1,38=9.527, P<.01
and F1,11=22.182, P<.001, respectively). No
gross motor abnormalities were noted at the time of testing, which was
a minimum of 3 weeks after the induction of global ischemia.
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Fig 2 shows a representation of the histological
damage produced by each duration of carotid occlusion, and Table 1 summarizes the degree of damage to each hippocampal
cell field. Significant group differences were observed for all
pyramidal cell fields measured (ANOVA: F3,70=676.02,
P<.001; F3,70=383.98, P<.001; and
F3,70=15.68, P<.001 for CA1, CA2, and CA3
pyramidal cells, respectively). Animals subjected to 5 minutes of
occlusion demonstrated significant cell loss to CA1 and CA2 pyramidal
cells, but cells in the CA3 region remained intact. Occlusion of the
common carotid arteries for 10 or 15 minutes resulted in a significant
reduction in the number of pyramidal cells in all regions measured. CA3
cell loss was significantly greater in animals exposed to 15 minutes of
carotid occlusion when compared with those occluded for 5 or 10
minutes.
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Effect of Lamotrigine on Reperfusion-Induced Cell Death
Histological analysis of the brains of untreated
gerbils examined 4 days after 5 minutes of bilateral occlusion of the
common carotid arteries showed an almost complete loss of hippocampal
CA1 pyramidal cells. Lamotrigine, when administered in two equal doses
of 30 mg/kg or 50 mg/kg 2 hours before and immediately after occlusion,
significantly prevented hippocampal CA1 cell loss (Fig 3A; ANOVA: F4,51=61.04, P>.001).
To a lesser degree, treating gerbils acutely with lamotrigine (100
mg/kg) immediately after reperfusion also afforded significant
protection to CA1 pyramidal cells (Fig 3B; ANOVA:
F3,28=8.25, P<.001). This protection, however,
was limited to treatment within 1 hour after reperfusion. When
administered at times greater than 1 hour after reperfusion,
lamotrigine failed to show significant protection of CA1 cells when
compared with untreated controls (Fig 3C).
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Effects of Lamotrigine on Water Maze Performance
Fig 4 shows that treatment with lamotrigine
significantly protected against the deficits in gerbil performance in
the Morris water maze produced by 15 minutes of bilateral carotid
occlusion (ANOVA: F2,43=8.666, P<.001). The
performance of treated animals was not different from that of
nonoccluded controls.
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Histological examination revealed that animals exposed to 15 minutes of
cerebral ischemia without any drug treatment experienced a significant
loss of neurons in the CA1, CA2, and CA3 regions of the hippocampus
(Table 2; ANOVA: F2,36=39.19,
P<.001; F2,36=29.66, P<.001; and
F2,36=10.91, P<.001 for CA1, CA2, and CA3
pyramidal cells, respectively). However, treatment with lamotrigine
afforded complete protection to the CA3 region of the hippocampus and
greatly reduced cell loss in the CA1 and CA2 cell regions.
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Lamotrigine also protected against mortality resulting from 15 minutes
of cerebral ischemia. Untreated animals subjected to 15 minutes of
bilateral carotid occlusion had a mortality rate of 66% compared with
23% mortality observed in lamotrigine-treated animals
(2=10.774, P<.005).
Plasma and Brain Levels of Lamotrigine at Doses That Protect
Against the Behavioral and Histological Consequences of Global
Ischemia
Table 3 shows the plasma and brain levels of
lamotrigine in gerbils after two 30-mg/kg doses of lamotrigine given
orally 2 hours apart or a single dose of 100 mg/kg given orally. In
both experiments the plasma and brain levels of lamotrigine rose
rapidly, and peak levels occurred within 30 minutes of dosing. The
levels of lamotrigine decreased slowly and only slightly during a
6-hour period. In the 100-mg/kg single-dose study, significant levels
were observed up to 24 hours after dosing.
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Discussion |
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Patients suffering from stroke, cardiac arrest, or traumatic brain injury, as well as patients undergoing cardiac and cardiopulmonary bypass surgery, commonly experience persistent neuropsychological dysfunction.1 2 3 4 5 6 Postmortem analyses of the brains of patients who have suffered cerebral ischemia or trauma reveal extensive neuronal damage to the CA1 pyramidal cells of the hippocampus,28 29 a region that is thought to play a critical role in learning and memory. This hippocampal damage has been related to memory impairments often suffered by these patients.28 29
The histological and behavioral effects of global cerebral ischemia in animals are similar to those observed in humans. In several rodent species, occlusion of the carotid arteries results in selective hippocampal damage, particularly to CA1 pyramidal cells. In rats, hippocampal damage associated with cerebral ischemia also is accompanied by impairments in tests measuring learning and memory.30 31 32 Although the gerbil has been extensively used as a model of global cerebral ischemia, the association between hippocampal cell damage and impairments in learning and memory in this species remains unclear. Gerbils exposed to 5 minutes of bilateral carotid occlusion fail to show impairment in the discrete lever-press avoidance and the discrete shuttle avoidance paradigms, despite complete degeneration of CA1 pyramidal neurons.33 34 Similarly, Corbett et al35 failed to find any lasting impairments in a Morris water maze task 21 days after 5 minutes of cerebral ischemia in the gerbil.
At the histological level, lamotrigine protected gerbils in our study from damage to hippocampal CA1 pyramidal cells resulting from 5 minutes of occlusion of the common carotid arteries. The drug was most effective when administered both before and immediately after occlusion. However, lamotrigine still afforded significant protection when administered acutely up to 1 hour after reperfusion.
The behavioral results from our study were consistent with the literature33 34 35 showing that 5 minutes of bilateral carotid occlusion in the gerbil fail to produce a deficit in a test of spatial memory 21 days after an ischemic insult. However, increasing the duration of bilateral carotid occlusion to 10 and 15 minutes resulted in increased deficits in water maze performance. Since damage to the CA1 pyramidal cells was complete with the ineffective 5-minute occlusion, these cognitive deficits are more likely correlated with cell loss elsewhere in the brain. We quantified such loss for the CA2 and CA3 sectors of the hippocampus. Our findings indicate that deficits observed in Morris water maze behavior in gerbils are not dependent on the degeneration of the CA1 cells of the hippocampus; they are more likely related to damage to other areas of the brain, possibly the CA2 and CA3 cells of the hippocampus.
Nevertheless, lamotrigine was effective in protecting against the cognitive deficit observed with 15 minutes of cerebral ischemia. After 15 minutes of ischemia, lamotrigine completely protected cells of the CA3 region of the hippocampus against the neurotoxic effects of ischemia. Approximately half of the CA1 and CA2 hippocampal cells remained intact in lamotrigine-treated gerbils undergoing this long interruption of blood supply. It is unlikely that this partial protection of CA1 pyramidal cells is responsible for the observed improvement in water maze behavior, since animals with complete destruction of CA1 cells show no deficits in this task. In addition to increasing cell survival, lamotrigine enhanced the survival rate of animals exposed to 15 minutes of bilateral carotid occlusion: lamotrigine-treated animals had a survival rate two times greater than that of untreated animals.
Lamotrigine does not cause a large reduction in body temperature, and artificial warming was used to maintain body temperature in our study. Nevertheless, it is possible that lamotrigine and anesthesia may have cooled gerbils more than anesthesia alone. This was not determined. For animals used in behavioral testing, cell counts were taken from brains harvested 45 days after carotid occlusion. This is important because hypothermia antagonizes CA1 cell death when cell counts are made on day 4 or 5 after reperfusion. Dietrich et al36 recently showed that hypothermia merely delays cell death. The 45-day period between occlusion and decapitation is sufficiently long to allow for completion of any cell death delayed by hypothermia.
The gerbil model of cerebral ischemia is not without other problems as well. Gerbils are susceptible to seizures in response to a variety of stimuli, such as handling or exposure to a novel environment.37 38 Prolonged seizure activity results in degeneration of hippocampal pyramidal neurons.39 For this reason, it would not be surprising for an antiepileptic drug to prevent cell loss during ischemia because of its anticonvulsant activity. Although seizure activity was not directly monitored in the present study, indications are that the neuroprotective effect of lamotrigine in this model was not owing to its ability to prevent seizures. The ED50 of lamotrigine for protecting against maximal electroshock-evoked hind limb extension in mice and rats is 2.6 mg/kg PO and 1.9 mg/kg PO, respectively.40 Doses in this range were ineffective in preventing ischemia-induced cell loss in our study. Also, several studies have suggested that seizure activity does not play a role in cell loss in gerbils during cerebral ischemia. Chon41 found that convulsive activity did not originate from the ischemic brain in gerbils. Also, postischemic measurment of CA1 cell activity in gerbils showed an increase in cell firing but not in convulsant activity.42 In a study by Suzuki et al,43 no signs of seizure activity were observed in gerbils exposed to 5 minutes of carotid occlusion.
The gerbils' responsiveness to novel environments and stimuli prompted us to make several modifications to the Morris water maze. For the first day of training, the water depth in the test apparatus was set at a level that permitted the gerbils to easily support themselves on the apparatus floor. Water depth on subsequent training days was adjusted, making the apparatus floor just out of reach of the gerbils when floating. These modifications allowed gerbils to readily acclimate to the novel test conditions, resulting in proficient ability of the animals to perform in the Morris water maze.
The antiepileptic effect of lamotrigine is believed to result from its ability to inhibit glutamate release.22 23 Lamotrigine significantly protects against kainic acid–induced neurotoxicity in rats, which is dependent on neuronally released glutamate.44 Leach et al22 23 found that lamotrigine specifically inhibits veratrine- but not K+-induced glutamate release, indicating the inhibition of voltage-sensitive sodium channels as the probable mechanism of action. The importance of sodium channels was shown by Lang et al,21 who demonstrated that lamotrigine inhibits use-dependent sodium channels in mouse neuroblastoma cells. Since glutamate appears to play a major role in the neuropathology observed in ischemia, the ability of lamotrigine to inhibit glutamate release by blocking voltage-sensitive sodium channels could also be the primary mechanism of action for its neuroprotective properties observed in the present study. However, inhibition of glutamate release cannot fully explain the neuroprotective effects observed with lamotrigine. Several studies indicate that extracellular glutamate levels peak during the ischemic period and return to normal levels within 30 minutes after reperfusion.10 45 Lamotrigine protected against ischemia-induced cell loss when administered 1 hour after reperfusion, well after peak extracellular glutamate levels are reached. This result suggests that lamotrigine activity in the present model cannot be explained solely by inhibition of glutamate release and that other mechanisms of action, perhaps its effect on use-dependent sodium channels,21 are involved.
Experience with lamotrigine use in the treatment of epilepsy indicates that plasma levels of 10 to 15 µg/mL are achieved in monotherapy patients.46 Results from the present study suggest that peak plasma levels of 27 µg/mL lamotrigine provide protection against cell damage produced by global ischemia in gerbils. These levels have not been reported during antiepileptic therapy in patients, and it is not clear if they would be achievable with acceptable side effects.
Received July 18, 1994; revision received October 11, 1994; accepted November 30, 1994.
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