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(Stroke. 1995;26:117-122.)
© 1995 American Heart Association, Inc.

Articles

Cerebroprotective Effect of Lamotrigine After Focal Ischemia in Rats

Stuart E. Smith, MSc, PhD Brian S. Meldrum, MB, BChir, PhD

From the Department of Neurology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, UK.

Correspondence to B.S. Meldrum, Department of Neurology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, SE5 8AF, UK.

	Abstract

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Background and Purpose Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine) is an anticonvulsant drug that blocks voltage-gated sodium channels and inhibits the ischemia-induced release of glutamate. We describe the cerebroprotective effect of lamotrigine (as the isethionate salt) after middle cerebral artery occlusion in rats.

Methods Neurological deficit and infarct volume (visualized by the lack of reduction of 2,3,5-triphenyltetrazolium chloride) 24 hours after permanent left middle cerebral artery occlusion were studied in Fischer rats (n=8 per group per dose).

Results Lamotrigine at 20 mg/kg IV over 10 minutes administered immediately after middle cerebral artery occlusion reduced total infarct volume by 31% and cortical infarct volume by 52%. Lamotrigine at 8 mg/kg IV over 10 minutes reduced cortical infarct volume by 38%. Lamotrigine at 50 mg/kg IV for 10 minutes was not cerebroprotective and induced a decrease of 29±15 mm Hg in mean arterial blood pressure (P<.05, n=8). The optimum dose of lamotrigine (20 mg/kg IV over 10 minutes) when administered with a 1-hour delay after middle cerebral artery occlusion reduced cortical infarct volume by 41%. Lamotrigine (20 mg/kg IV over 10 minutes) with a 2-hour delay after middle cerebral artery occlusion was ineffective. Neurological deficits after 24 hours were improved after immediate treatment with lamotrigine at 20 mg/kg IV over 10 minutes.

Conclusions The cerebroprotective effect of lamotrigine in rats is limited to a narrow dose range between 8 and 20 mg/kg. Lamotrigine or analogous compounds may be useful when given shortly after the onset of stroke.

Key Words: cerebral ischemia • sodium channels • neuroprotection • glutamates • rats

	Introduction

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The activation of excitatory amino acid receptors is thought to be involved in the development of infarction of cerebral tissue.^{1 2} During focal cerebral ischemia, augmented concentrations of glutamate and aspartate (peaking at 0.5 to 2 hours after occlusion) have been detected in the extracellular space using microdialysis techniques.^{3 4 5 6} Based on electrophysiological studies, postsynaptic ionotropic receptors for excitatory amino acids at which glutamate may act are classified into three main subtypes.⁷ These comprise the receptors preferring N-methyl-D-aspartate (NMDA), kainate, and S--amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). AMPA and kainate receptors are referred to as "non-NMDA receptors." Glutamate has excitotoxic effects acting via NMDA or non-NMDA receptors in vivo and in vitro.^{8 9} Cerebroprotection with excitatory amino acid antagonists acting at NMDA and non-NMDA receptors has been established after focal cerebral ischemia.^{2 10 11 12 13 14 15 16 17 18 19} An alternative approach is to reduce the release of glutamate during and after the ischemic insult.^{20 21 22 23}

Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine; Lamictal) is a novel anticonvulsant agent with efficacy in patients with partial seizures or generalized tonic clonic seizures. The time course for the anticonvulsant effect for lamotrigine in animals and in photosensitive epileptic patients is relatively long (from 1 to 24 hours) after intravenous, intraperitoneal, or oral administration. Lamotrigine is completely bioavailable after oral administration in rats and is distributed throughout the body; anticonvulsant doses of 2 to 4 mg/kg result in plasma concentrations of lamotrigine of 1 to 2 µg/mL. Lamotrigine is rapidly absorbed, and its half-life for elimination in the Wistar rat is 12 to 15 hours.^{24 25 26 27 28}

The mechanism of anticonvulsant action of lamotrigine is thought to involve action at voltage-sensitive sodium channels.^{29 30 31} Lamotrigine reduces veratrine- but not K⁺-induced glutamate, aspartate, and -aminobutyric acid release with ED₅₀ values of 21 µmol/L, 21 µmol/L, and 44 µmol/L, respectively, in cerebrocortical slices from the rat in vitro.^{24 25 28} Lamotrigine has no effect on the binding of a wide range of radiolabeled neurotransmitters (including dopamine D₁ and D₂; adrenergic ₁, ₂, and ß; adenosine A₁ and A₂; muscarinic; or binding sites), but it does compete with [³H]batrachotoxinin-A-20--benzoate (pK_i=3.5),^{25 30} a ligand interacting with a sodium channel site related to activation of sodium channel fluxes, and with [³H]quipazine (pK_i=5.7), a ligand interacting with 5-HT₃ recognition sites.²⁵

The present study was designed to determine whether lamotrigine has cerebroprotective effects after permanent left middle cerebral artery (MCA) occlusion in rats. Preliminary data have been presented.^{32 33 34}

	Materials and Methods

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Adult male Fischer F344 rats weighing 250 to 310 g were housed in groups of four to six in polyvinylchloride cages (350 mm widex530 mm longx180 mm high) in an environment maintained at 19°C to 22°C and a relative humidity of 55±3%, respectively, with a 14-h light/10-h dark cycle (light on from 6 AM to 8 PM). Food and water were available ad libitum. Halothane was used to induce (4% in a mixture of 70% N₂O and 30% O₂) and maintain (2%) anesthesia. Each rat was allowed to breathe spontaneously, and rectal temperature was maintained at 37°C (36.5°C to 38°C) with a heating blanket. The left femoral vein was cannulated for drug administration, and the caudal (tail) artery was cannulated for the continuous monitoring of arterial blood pressure, repeated blood sampling for serial measurements of blood glucose concentration, PaO₂, PaCO₂, and pH levels. Arterial blood (200 µL total volume) was collected without the need for induced negative pressure from the caudal artery of the rats for immediate analysis at 15 minutes before and 15 minutes after MCA occlusion and in some experiments at 30-minute intervals thereafter. Blood gases and pH were analyzed using an IL13404 analyzer (Instrumentation Laboratories), and blood glucose level was measured with Glucostix strips (Bayer Diagnostics, Ames Division). The temperature of the exposed temporalis muscle was monitored using a thermoprobe.

All rats underwent subtemporal subperiosteal craniectomy (with intact zygoma) and exposure of the main trunk of the left MCA under 25-fold magnification of an operating stereomicroscope.^{35 36} The exposed artery was electrocauterized from a point proximal to the lenticulostriate branch(es) to its junction with the inferior cerebral vein.

The rats received in a blinded fashion vehicle (0.25% wt/vol methylcellulose [Sigma Chemical Co], 400 cp, in high-performance liquid chromatography water) or lamotrigine (3.2, 8, 20, or 50 mg/kg IV over 10 minutes; 1 mL/kg; all doses refer to the isethionate salt of lamotrigine) immediately after MCA occlusion (n=8 per group per dose). In a further experiment, vehicle or lamotrigine (20 mg/kg IV over 10 minutes) was administered 1 or 2 hours after MCA occlusion (n=8). During the 10-minute infusions and the 1- or 2-hour delay, rats were lightly anesthetized with 0.5% halothane in a mixture of 70% N₂O and 30% O₂. Fifteen minutes after MCA occlusion or 5 minutes after the delayed infusion, the cannulas were removed, the anesthesia was discontinued, and the animals were allowed to recover in cages warmed with an overhead lamp (60-W bulb, 30-cm distance). Rectal temperature was measured at +1 hour after vehicle or drug infusion.

Twenty-four hours after MCA occlusion, the rats were assessed in a blinded fashion for neurological deficits based on the rating scales used by Bederson et al³⁷ and Germano et al.¹⁰ The following grading scale was used: grade 0, no observable deficit; grade 1, forelimb flexion; grade 2, forelimb flexion and decreased resistance to lateral push; and grade 3, forelimb flexion, decreased resistance to lateral push, and unilateral circling in three successive trials. The animals were then decapitated, and the brain was rapidly removed (within 2 minutes), examined for proximal MCA occlusion, and then placed into a vibratome containing saline at 8°C. Ten coronal sections (1 mm thick) were cut from the frontal pole and then incubated for 30 minutes in microwells, each containing 2 mL 2% wt/vol triphenyltetrazolium chloride in saline at 37°C before storage in 0.1 mol/L phosphate-buffered (pH 7.4) 5% vol/vol formaldehyde in saline for 1 to 5 days. The sections were photographed to scale, and slides were prepared and used to estimate the left and right hemispheric and the total, cortical, and noncortical infarct areas using an IBAS image analyzer (Kontron Elektronik, GmbH). These areas were used to calculate the hemispheric and infarct volumes in cubic millimeters by use of a BASIC integration program that is based on the ends of spheres and truncated cones. Infarct volumes are expressed as mean±SD and were analyzed using Student's unpaired t test or Dunnett's test (SAS/STAT version 6). Neurological deficit is expressed as frequency for observed deficit and was analyzed using an unpaired rank test. Rectal and temporalis temperatures, blood pressure, glucose, and gases, and pH recorded during the experiment were analyzed using MANOVA.

	Results

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There was a consistent pattern of ischemic brain damage after permanent MCA occlusion. Lesions were seen in the dorsolateral frontoparietal cortex, the caudate putamen, and the globus pallidus. The boundaries between the areas of infarction and the normal adjacent areas were sharply demarcated.

Immediate Administration of Lamotrigine
Immediate postocclusion infusion of lamotrigine (3.2 mg/kg IV over 10 minutes) did not significantly reduce the total, cortical, or noncortical infarct volumes (Fig 1). Neurological deficit was not reduced (Fig 2; vehicle score, 1.8±0.5; lamotrigine score, 1.5±0.9; P>.05). Immediate postocclusion infusion of lamotrigine (8 mg/kg IV over 10 minutes) reduced the cortical infarct volume by 38% (from 50±15 mm³ in vehicle-treated to 31±11 mm³ in lamotrigine-treated rats; P<.05). Total and noncortical infarct volumes were not significantly reduced (Fig 1). Neurological deficit was not reduced (Fig 2; vehicle score, 1.8±0.5; lamotrigine score, 1.6±0.5; P>.05).

View larger version (33K): [in this window] [in a new window]   Figure 1. Bar graph showing infarct volumes 24 hours after middle cerebral artery (MCA) occlusion. Rats received 10-minute infusions of either vehicle or lamotrigine isethionate (3.2, 8, 20, or 50 mg/kg IV) immediately, or vehicle or lamotrigine isethionate (20 mg/kg IV) 1 hour or 2 hours after MCA occlusion. Values are mean±SD infarct volumes in cubic millimeters. Significant reduction in infarct volume after lamotrigine isethionate administration by Student's unpaired t test with the respective vehicle-treated group (n=8); * P<.05; ** P<.01. Tot indicates total; C, cortical; and NC, noncortical.

View larger version (66K): [in this window] [in a new window]   Figure 2. Stacked bar graph showing neurological scores of rats 24 hours after middle cerebral artery (MCA) occlusion. Rats received 10-minute infusions of vehicle (Veh) or lamotrigine isethionate (3.2, 8, 20, or 50 mg/kg IV) immediately, or vehicle or lamotrigine isethionate (20 mg/kg IV) 1 hour or 2 hours after MCA occlusion. Bars show the numbers of rats with observed neurological scores of 0 to 3. Significant reduction in neurological deficit by unpaired rank test; *P<.05.

Immediate postocclusion infusion with lamotrigine (20 mg/kg IV over 10 minutes) reduced the total infarct volume by 31% (from 118±33 mm³ in vehicle-treated to 81±38 mm³ in lamotrigine-treated rats; P<.05). Cortical infarct volume was reduced by 52% (from 50±15 mm³ in vehicle-treated to 24±15 mm³ in lamotrigine-treated rats; P<.05). Noncortical infarct volume was not significantly reduced (Fig 1). Neurological deficit was also reduced (Fig 2; vehicle score, 1.8±0.5; lamotrigine score, 0.8±0.7; P<.05). Temporalis temperature rose by 1°C in the lamotrigine-treated group 15 minutes after MCA occlusion (P<.05).

Immediate postocclusion infusion with lamotrigine (50 mg/kg IV over 10 minutes) did not significantly reduce the total, cortical, or noncortical infarct volumes (Fig 1). Neurological deficit was not reduced (Fig 2; vehicle score, 1.8±0.5; lamotrigine score, 1.5±0.5; (P>.05).

1-Hour Delay Before Administration of Lamotrigine
Delayed (1 hour) postocclusion infusion with lamotrigine (20 mg/kg IV over 10 minutes) reduced cortical infarct volume by 41% (from 56±25 mm³ in vehicle-treated to 33±17 mm³ in lamotrigine-treated rats; P<.05). The total and noncortical infarct volumes were not significantly reduced (Fig 1). Neurological deficit was not reduced (Fig 2; vehicle score, 1.8±0.5; lamotrigine score, 1.4±0.5; P>.05).

2-Hour Delay Before Administration of Lamotrigine
Delayed (2 hours) postocclusion infusion with lamotrigine (20 mg/kg IV over 10 minutes) had no effect on total, cortical, or noncortical infarct volume (Fig 1). Neurological deficit was not reduced (Fig 2; vehicle score, 1.8±0.5; lamotrigine score, 1.4±0.6; P>.05).

Adverse Effects
Lamotrigine (3.2 to 20 mg/kg IV over 10 minutes) induced no significant changes in blood gases, pH, or glucose levels, mean arterial blood pressure, or rectal or temporalis temperature (n=8).

Lamotrigine (50 mg/kg IV over 10 minutes) induced a reduction of 29±15 mm Hg in mean arterial blood pressure compared with vehicle-treated rats (P<.05; Student's unpaired t test). A regression and correlation analysis of the drop of blood pressure against infarct volume (total, cortical, or noncortical) in each rat showed no significant correlation between changes in blood pressure and infarct volume (n=8). Other physiological variables were unaffected (n=8).

On recovery from anesthesia, the animals displayed no adverse behavioral effects after the 10-minute infusion of 3.2, 8, or 20 mg/kg of lamotrigine isethionate. Severe impairment of locomotor coordination (duration, 5 to 8 hours) was observed after the 10-minute infusion of 50 mg/kg of lamotrigine.

For all groups, rectal temperatures were similar, ranging between 36.8°C and 37.5°C. Temporalis temperature was lower, ranging between 32.5°C and 33.9°C.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Lamotrigine (20 mg/kg) reduces total and cortical infarct volume and improves neurological deficit in rats when administered immediately after MCA occlusion. After delayed (+1 hour) administration of lamotrigine (20 mg/kg), cortical infarct volume was significantly reduced. Neurological deficit was unaffected. The therapeutic time window for a cerebroprotective effect coincides with the peak increase of extracellular concentrations of glutamate and aspartate, which occurs 0.5 to 2 hours after occlusion during focal cerebral ischemia.^{3 4 5 6}

Neuronal cell loss after focal injection of kainate into the striatum of the rat is thought to be mediated by the release of neuronal glutamate.³⁸ Lamotrigine (8 to 16 mg/kg IP) at similar doses as those used in this study protects against kainate neurotoxicity in rat striatum.³⁹

Reduction of cortical infarct volume has been described with compounds with chemical structure similar to lamotrigine, which also block sodium channels and inhibit glutamate release: BW1003C87 (5-[2,3,5-trichlorophenyl]-2,4-diaminopyrimidine ethane sulphonate; 20 mg/kg IV for 5 minutes) administered immediately after permanent MCA occlusion in rats^{20 21} and BW619C89 (4-amino-2-[4-methylpiperazine-1-yl]-5-[2,3,5-trichlorophenyl]pyrimidine; 5 to 30 mg/kg IV for 5 to 10 minutes.^{22 23}

Other compounds with an ability to block sodium channels or to inhibit ischemia-induced glutamate release, which both reduce cortical infarct volume in models of focal cerebral ischemia in the rat, include the -opiate agonist CI-977 (enadoline; [5R]-[5, 7, 8ß]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-(4,5)-dec-8-yl]-4-benzofuranacetamide · HCl),^{40 41} riluzole,^{42 43} and phenytoin.⁴⁴ Basal microdialysate concentrations of glutamate are unaffected by lamotrigine,²⁵ BW1003C87,^{20 45} or CI-977.⁴⁶

BW1003C87 and BW619C89 are more potent inhibitors of veratrine-induced glutamate release than lamotrigine and are also cerebroprotective in rat models of transient forebrain ischemia.^{23 45} Lamotrigine exhibits a bell-shaped dose-response curve for cerebroprotective effect after MCA occlusion in rats. The optimally effective dose is 20 mg/kg, which is 10-fold the anticonvulsant dose in rats (anticonvulsant ED₅₀ values against maximal electroshock-induced or sound-induced seizures are 2 mg/kg).^{24 25 26}

When administered before or during focal cerebral ischemia, lamotrigine, BW1003C87, or BW619C89 reduce the ischemia-induced release of glutamate.^{21 23 34} The clinical use of BW1003C87 is limited by its ability to inhibit dihydrofolate reductase, which could lead to anemia, thrombocytopenia, and teratogenicity. Lamotrigine congeners like BW619C89, which inhibit ischemia-induced release of glutamate, may provide a novel approach for the therapy of stroke. The precise site and mechanism of the cerebroprotective effect of lamotrigine, BW1003C87, and BW619C89 have not yet been identified. Evidence suggests that an interference with sodium flux across neuronal membranes may be the basis of the anticonvulsant and cerebroprotective effects of these compounds.^{28 29 30 31} A primary action and use-dependent blockade at sodium channels may result in a number of effects: (1) inhibition of high-frequency neuronal firing rate, resulting in less glutamate release;^{29 31} (2) prevention of an ischemia-induced anoxic depolarization that is characterized by an intraneuronal accumulation of sodium, calcium, and chloride ions;⁸ (3) maintenance of the intracellular and extracellular sodium gradient that contributes to the outward movement of Ca²⁺ (via the Na⁺/Ca²⁺ exchanger) and the inward movement of glutamate (via the Na⁺-coupled glutamate transporter);⁴⁷ (4) prevention of cytotoxic edema that occurs after ischemia; and (5) inhibition of spreading depression that may be an indicator or determinant of the process of infarction.⁴⁸

Comparable degrees of cerebroprotection are observed with representative compounds from the following classes of glutamate antagonists: competitive NMDA (D-[E]-4-[3-phosphonoprop-2-enyl]piperazine-2-carboxylic acid [D-CPPene]), uncompetitive NMDA (MK801), and non-NMDA antagonists (NBQX and GYKI52466) after focal cerebral ischemia in rats.^{2 10 11 12 13 14 15 16 17 18 19} These compounds have minimum effective doses in animal models of stroke that are close to doses that induce adverse effects (impairment of locomotor performance, hypotension, respiratory depression). Analogues of these compounds with fewer adverse effects may be developed. Lamotrigine and BW619C89 have a greater separation between effective doses in animal models of stroke and doses that induce adverse effects.^{49 50}

Adverse neurological effects were observed after intravenous administration of 50 mg/kg lamotrigine to rats in the present study; cerebroprotection was observed with 20 mg/kg IV lamotrigine, a dose that did not induce any evident adverse behavioral effects. Doses of lamotrigine above 20 mg/kg may have less cerebroprotective effect than a dose of 20 mg/kg because of the increased likelihood of hypotensive effects.

The present data confine the therapeutic time window with lamotrigine to less than 2 hours after the onset of stroke in rodents. Infarction after MCA occlusion develops more slowly in primates, suggesting that the therapeutic time window may be longer in humans.⁵¹

These studies suggest that compounds of this class may be useful in the treatment of stroke and related neurodegenerative disorders.

	Acknowledgments

 
This study was supported by the Bethlem Maudsley Research Fund, the Medical Research Council of Great Britain, and the Wellcome Foundation. We thank Dr M. Leach from the Wellcome Research Centre, Beckenham, Kent, for the supply of lamotrigine and for his scientific comments on the manuscript.

Received March 7, 1994; revision received August 11, 1994; accepted September 20, 1994.

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