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NEUROPHARMACOLOGY

Effects of Lamotrigine Alone and in Combination with MK-801, Phenobarbital, or Phenytoin on Cell Death in the Neonatal Rat Brain

Departments of Pediatrics (I.K., A.K.) and Pharmacology (J.K., K.G., A.K.) and Interdisciplinary Program in Neuroscience (J.K., K.G., A.K.), Georgetown University Medical Center, Washington, DC

Received March 20, 2007; accepted May 3, 2007.

	Abstract

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The neonatal rat brain is vulnerable to neuronal apoptosis induced by antiepileptic drugs (AEDs), especially when given in combination. This study evaluated lamotrigine alone or in combination with phenobarbital, phenytoin, or the glutamate antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) for a proapoptotic action in the developing rat brain. Cell death was assessed in brain regions (striatum, thalamus, and cortical areas) of rat pups (postnatal day 8) by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, 24 h after acute drug treatment. Lamotrigine alone did not increase neuronal apoptosis when given in doses up to 50 mg/kg; a significant increase in cell death occurred after 100 mg/kg. Combination of 20 mg/kg lamotrigine with 0.5 mg/kg MK-801 or 75 mg/kg phenobarbital resulted in a significant increase in TUNEL-positive cells, compared with MK-801 or phenobarbital treatment alone. A similar enhancement of phenytoin-induced cell death occurred after 30 mg/kg lamotrigine. In contrast, 20 mg/kg lamotrigine significantly attenuated phenytoin-induced cell death. Lamotrigine at 10 mg/kg was without effect on apoptosis induced by phenytoin. Although the functional and clinical implications of AED-induced developmental neuronal apoptosis remain to be elucidated, our finding that lamotrigine alone is devoid of this effect makes this drug attractive as monotherapy for the treatment of women during pregnancy, and for preterm or neonatal infants. However, because AEDs are often introduced as add-on medication, careful selection of drug combinations and doses may be required to avoid developmental neurotoxicity when lamotrigine is used in polytherapy.

Because excessive neuronal loss in the late prenatal or early postnatal development may contribute to long-term adverse effects, it is important to identify treatment regimens that are devoid of this deleterious action. Because neonatal seizures are aggressively treated with AEDs and AEDs cannot be given to healthy infants to serve as controls, AED-induced neuronal apoptosis in the neonatal rat represents an ideal animal model for addressing this challenge. Using this model, several second generation AEDs (i.e., topiramate and levetiracetam) have been recently examined for their effects in the immature rat brain following acute administration (Glier et al., 2004; Manthey et al., 2005; Kim et al., 2006, 2007). The results in this animal model are relevant not only to neonates but also to the third trimester of human gestation.

One of the second generation AEDs of particular interest is lamotrigine (LTG). LTG is a widely used, well tolerated AED that is effective against most types of seizures (for review, see Bialer et al., 2007). LTG has been recently introduced as an effective treatment for bipolar mood disorders (Hahn et al., 2004; Gao and Calabrese, 2005). LTG exerts its action by blocking voltage-gated sodium channels, thereby modulating presynaptic excitatory neurotransmitter release (White, 1999). LTG has been reported to have neuroprotective capacity (Willmore, 2005). To date, the effect of LTG on neuronal cell death in neonatal rats has not been determined. Accordingly, in the current study, we examined the effect of single administration of LTG (10–100 mg/kg) on neurodegeneration in several brain regions of neonatal rats. In addition to examining the effect of LTG when given alone, we also determined whether it can exacerbate the cell death induced by traditional AEDs. This is an important issue because AEDs in combination have been found to exert a synergistic effect on cell death in the immature brain (Bittigau et al., 2002; Kim et al., 2006). Therefore, we also examined the effects of LTG given in combination with phenytoin, phenobarbital, or MK-801. These drugs were selected because they act through different mechanisms of action: phenytoin by blocking sodium channels, phenobarbital by enhancing GABA_A receptor function, and MK-801 by noncompetitive blockade of NMDA-type glutamate receptors. We report that acute administration of LTG alone in the therapeutic range of doses does not induce neuronal cell death in rat pups. However, combination of LTG with certain doses of phenytoin, phenobarbital, or MK-801 resulted in amplification of neurodegeneration.

View larger version (39K): [in this window] [in a new window]   Fig. 1. Areas of the brain examined for drug-induced neurodegeneration are marked by rectangles.

	Materials and Methods

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Experimental Design. Effects of LTG [Lamictal, 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine; GlaxoSmithKline, Research Triangle Park, NC] alone on cell death were examined. The following drug combinations were also tested: LTG + MK-801, LTG + phenobarbital (Luminal, 5-ethyl-5-phenyl-1,3-diazinane-2,4,6-trione), and LTG + phenytoin (sodium diphenylhydantoin, 5,5-diphenylimidazolidine-2,4-dione) (Sigma-Aldrich, St. Louis, MO). MK-801, phenobarbital, and phenytoin given alone were also evaluated. Each experimental and control group was made up of pups from at least two different litters; pups from a given litter were distributed across each of the different experimental groups (controls, individual drugs, and drug combinations). Male and female pups likewise were distributed across groups to create as much balance as possible. Cell death was evaluated in coronal brain sections by TUNEL assay (see below) in several brain areas, including striatum, thalamus, multiple cortical regions, and the hippocampus (refer to Fig. 1 for the location of the brain areas examined).

Drug Treatment. All drugs were administered i.p. to pups at PD7, the age of peak vulnerability to drug-induced cell death. LTG (10, 20, 30, 50, or 100 mg/kg; n = 2, 13, 8, 7, and 4 rats/group, respectively) was administered in saline containing 1% polysorbate 80, polyoxyethylene sorbitan monooleate (Tween 80). Control groups received saline containing 1% Tween 80. MK-801 (0.5 mg/kg; n = 4; Sigma-Aldrich, St. Louis, MO), phenytoin (50 mg/kg; n = 9; SigmaAldrich), and phenobarbital (75 mg/kg; n = 6; Sigma-Aldrich) were injected in saline, except for phenytoin, which was dissolved in alkalinized saline, pH 9 to 11.

For drug combination studies, MK-801, phenobarbital, or phenytoin was given at T =–2 h, LTG was given as above at T = 0 h, and animals were sacrificed and brain samples were collected on PD8 at T = 24 h. Control groups for drug combination studies received appropriate vehicle injections (normal or alkalinized saline) at T = –2 h and a second injection of normal saline containing 1% Tween 80 at T = 0 h. The numbers of animals used for the drug combinations are indicated in Table 1; the number of litters that contributed to each group is indicated in parentheses.

Tissue Preparation. Brains were rapidly removed, they were quickly frozen in isopentane, and then they were stored at –80°C until further processing. Coronal cryostat sections (20 µm) were prepared throughout the brain and examined for cell death using TUNEL assay (see below).

Histology and Quantification. To measure apoptotic cell death, TUNEL staining was performed using the Apoptag peroxidase in situ apoptosis detection kit (Chemicon International, Temecula, CA) as described previously (Kim et al., 2006). Staining was examined in photomicrographs (10x) of three sequential sections at 200-µm intervals taken from several brain areas; quantification of cell death was performed in the brain areas that exhibited the greatest degeneration across treatments. These areas included ventromedial and dorsolateral portions of thalamus, the dorsomedial portion of anterior striatum, and the cortex (frontal, parietal, or retrosplenial) of each animal. Except for the hippocampus, TUNEL-positive cells were counted within 1.00 mm² regardless of size and shape. In the hippocampus, the total number of TUNEL positive cells within each section was counted. Quantification was performed by an observer blinded to the treatment conditions.

View larger version (68K): [in this window] [in a new window]   Fig. 2. A, effect of LTG on cell death as indicated by the number of TUNEL-positive cells 24 h following administration of LTG (10, 20, 30 50, or 100 mg/kg) to PD7 rat pups. LTG (0 mg/kg) indicates vehicle-treated control. Values are expressed as mean ± S.E.M. per tissue section. Asterisk (*) indicates significant difference, compared with vehicle-treated control (ANOVA with Tukey's post hoc test; p < 0.05). B, representative photomicrographs taken in the area of dorsomedial striatum 24 h following vehicle injection (a), 20 mg/kg LTG (b), 30 mg/kg LTG (c), and 100 mg/kg LTG (d). TUNEL-positive cells are seen as brown spots on a blue-gray background. Scale bar, 100 µm.

Statistics. Statistical comparisons were performed by ANOVA followed by post hoc Tukey's test with p < 0.05 indicating significant difference.

	Results

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Administration of LTG Alone. LTG alone administered at doses of 10 to 30 mg/kg did not induce significant cell death in any of the brain areas examined (Fig. 2), as assessed by TUNEL assay. At a dose of 50 mg/kg, 43% of the animals showed increased cell death in lateral thalamus. Administration of 100 mg/kg resulted in significant increase in cell death in all brain areas examined except frontal cortex. We also evaluated the tissue using Fluoro-Jade B staining, which selectively detects neuronal degeneration. The Fluoro-Jade B staining profiles were consistent with TUNEL assay results (data not shown).

Administration of LTG in doses of 10 to 50 mg/kg did not affect growth of the pups during the 24 h after drug injection, and was the pups were devoid of acute behavioral effects except for occasional signs of ataxia immediately after a 50-mg/kg dose. A dose of 100 mg/kg resulted in weight loss 24 h after the injection (weight change: +2.0 ± 0.23 g, vehicle-treated controls; –1.3 ± 0.19 g, LTG; p < 0.05).

Combined Administration of LTG with MK-801. To determine whether LTG can modify the cell death-promoting effect of the NMDA receptor antagonist MK-801 (Ikonomidou et al., 1999), we administered 20 mg/kg LTG in combination with 0.5 mg/kg MK-801. We selected a dose of 20 mg/kg, which is equivalent to the upper end of the therapeutic range of LTG for pediatric applications (GlaxoSmithKline, 2006). This combination caused significantly more cell death in striatum and frontal cortex than that induced by MK-801 alone (Fig. 3). A trend toward such potentiation was observed in the ventral and lateral thalamus.

View larger version (64K): [in this window] [in a new window]   Fig. 3. A, amplification of MK-801-induced cell death following combined administration of 0.5 mg/kg MK-801 with 20 mg/kg LTG. MK-801 was administered 2 h before LTG as described under Materials and Methods. Cell death is indicated by the number of TUNEL-positive cells 24 h following administration of 20 mg/kg LTG to PD7 rat pups. VEH, vehicle-treated control. Values are expressed as mean ± S.E.M. in 1.0 mm2 per tissue section. Asterisk (*) indicates significant difference, compared with vehicle-treated control; , significant difference, compared with 20 mg/kg LTG alone; and #, significant difference, compared with 0.5 mg/kg MK-801 alone (ANOVA with Tukey's post hoc test; p < 0.05). B, representative photomicrographs taken in the area of dorsomedial striatum 24 h following vehicle injection (a), 20 mg/kg LTG (b), 0.5 mg/kg MK-801 (c), 0.5 mg/kg MK-801 + 20 mg/kg LTG (d), 75 mg/kg phenobarbital (e), and 75 mg/kg phenobarbital + 20 mg/kg LTG (f). TUNEL-positive cells are seen as brown spots on a blue-gray background. Scale bar, 100 µm.

Combined Administration of LTG with Phenobarbital. To determine whether LTG potentiates cell death induced by a traditional AED, we examined the effect of 20 mg/kg LTG on the proapoptotic action of phenobarbital.

Combined treatment with 20 mg/kg LTG and 75 mg/kg phenobarbital resulted in a significantly greater number of TUNEL-positive cells in striatum and lateral thalamus, compared with that seen after phenobarbital alone (Fig. 4). A trend toward similar potentiation was observed in the ventral thalamus, frontal cortex, and retrosplenial cortex.

View larger version (62K): [in this window] [in a new window]   Fig. 4. Amplification of phenobarbital-induced cell death following combined administration of 75 mg/kg phenobarbital (PB) with 20 mg/kg LTG. Phenobarbital was administered 2 h before LTG as described under Materials and Methods. Cell death is indicated by the number of TUNEL-positive cells 24 h following administration of 20 mg/kg LTG to PD7 rat pups. Values are expressed as mean ± S.E.M. in 1.0 mm2 per tissue section. Asterisk (*) indicates significant difference, compared with vehicle-treated control; , significant difference, compared with 20 mg/kg LTG alone; #, significant difference, compared with 75 mg/kg phenobarbital alone (ANOVA with Tukey's post hoc test; p < 0.05). B, representative photomicrographs taken in the area of dorsomedial striatum 24 h following vehicle injection (a), 20 mg/kg LTG (b), 75 mg/kg phenobarbital (c), and 75 mg/kg phenobarbital + 20 mg/kg LTG (d). TUNEL-positive cells are seen as brown spots on a blue-gray background. Scale bar, 100 µm.

Combined Administration of LTG with Phenytoin. In contrast to the combined action with phenobarbital and MK-801, combined application of 20 mg/kg LTG with 50 mg/kg phenytoin attenuated the phenytoin-induced cell death. Whereas phenytoin alone enhanced significantly the number of TUNEL-positive cells in striatum, ventral and lateral thalamus, and retrosplenial cortex, the presence of 20 mg/kg LTG prevented this phenytoin-induced enhancement of cell death (Fig. 5).

View larger version (73K): [in this window] [in a new window]   Fig. 5. Effect of combined application of 10, 20, or 30 mg/kg lamotrigine on phenytoin-induced cell death. Phenytoin (PHE; 50 mg/kg) was administered 2 h before LTG as described under Materials and Methods. Cell death is indicated by the number of TUNEL-positive cells 24 h following administration of 20 mg/kg LTG to PD7 rat pups. Values are expressed as mean ± S.E.M. in 1.0 mm2 per tissue section. Asterisk (*) indicates significant difference, compared with vehicle-treated control; #, significant difference, compared with 50 mg/kg phenytoin alone (ANOVA with Tukey's post hoc test; p < 0.05). B, representative photomicrographs taken in the area of dorsomedial striatum 24 h following 20 mg/kg LTG (a), 50 mg/kg phenytoin (b), 50 mg/kg phenytoin + 20 mg/kg LTG (c), and 50 mg/kg phenytoin + 30 mg/kg LTG (d). TUNEL positive cells are seen as brown spots on a blue-gray background. Scale bar, 100 µm.

Lower and higher doses of LTG (10 and 30 mg/kg, respectively) did not attenuate the phenytoin-induced cell death effect in any region examined. In contrast, there was a trend for 30 mg/kg LTG to potentiate the action of phenytoin in most of the brain areas examined.

Administration of phenytoin alone or in combination with LTG (10 or 20 mg/kg) did not result in significant changes in animal weight gain and behavior; phenytoin in combination with a high dose (30 mg/kg) of LTG impaired weight gain (0.0 ± 0.28 g), compared with vehicle-treated controls (+2.0 ± 0.23 g), and it caused occasional ataxia.

Comparison of Male and Female Pups. When collapsed across the various drug treatments that induced significant apoptotic cell death, there was no significant difference between response in male and female pups. The one case in which a tendency toward sex differences was noted was in the combination 20 mg/kg LTG + phenytoin (four females, four males) in which the reduction in cell death due to LTG seemed to be largely due to an effect on females (70% reduction of the phenytoin-induced increase in striatum, 81% reduction of the phenytoin-induced increase in lateral thalamus, and 79% reduction of the phenytoin-induced increase in ventral thalamus).

	Discussion

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In this study, we have demonstrated that single administration of LTG does not induce apoptotic neurodegeneration in the neonatal rats when administered alone in doses at or above those effective for preventing seizures in a variety of rodent models (Dalby and Nielsen, 1997; Yamashita et al., 2004; Shannon et al., 2005) and equivalent to doses at or above the therapeutic range in humans (GlaxoSmithKline, 2006). Although higher doses of LTG (i.e., 50 and 100 mg/kg) caused widespread neuronal cell death, these doses are not likely to be used therapeutically.

Of particular importance is our observation that combined application of LTG with phenobarbital results in a significant enhancement of the proapoptotic action of phenobarbital. The observation of a synergistic effect of combined AED administration in the neonatal rats on apoptotic neuronal death is reminiscent of previously reported findings with other AED combinations. In particular, diazepam enhanced neonatal neuronal apoptosis induced by phenobarbital or phenytoin when given in subthreshold doses (Bittigau et al., 2002). We have shown recently that doses of topiramate and carbamazepine that were without toxicity when given alone potentiated neurodegeneration induced by phenytoin (Kim et al., 2006). Thus, that an individual AED does not induce neonatal apoptotic cell death when given alone does not predict that the drug will be devoid of toxicity when given in combination with additional AEDs.

Our finding that combined application of LTG with MK-801 causes an enhancement of the proapoptotic action of MK-801 as well as that of phenobarbital suggests that the potentiation of proapoptotic action by LTG is not dependent on the specific mechanism of action of the proapoptotic compound. This is consistent with the "underactivation" hypothesis of developmental apoptosis, which predicts that suppression of neuronal activity predisposes to cell death during a critical developmental period. This suppression can be achieved either by inhibition of NMDA-type glutamate receptors (e.g., by MK-801) or by overactivation of the GABAergic system (achieved by a GABA mimetics) (Olney, 2002). The fact that enhanced sedation and slower growth were associated with the combined drug application is consistent with the possibility that LTG potentiated the suppression of neuronal activity by MK-801 and phenobarbital.

An unexpected finding in the present study is the effect of 20 mg/kg LTG on the phenytoin-induced apoptosis. The apparent protective action of LTG was unusual in that it was highly dose-specific; the effect was seen neither with 10 or 30 mg/kg. Moreover, the effect tended to be more pronounced in female than male pups, raising the possibility that our data underestimate the maximal potential for this apparent neuroprotection. It is possible that LTG may have a biphasic effect on neuronal apoptosis: a mild antiapoptotic property, which is insufficient to be detected at low doses of LTG (e.g., 10 mg/kg), and a proapoptotic property, which becomes detectable at doses equal to (when given in combination with phenytoin) or above (when given alone) a dose of 30 mg/kg. This proposition is supported by the fact that we have found a trend toward lowering the baseline apoptosis in several brain regions following treatment with 10 and 20 mg/kg LTG alone, whereas the trend toward enhancing baseline apoptosis has been observed following 30 mg/kg LTG regimen. The trend toward enhancing phenytoin effects with 30 mg/kg LTG also supports this possibility. It is tempting to speculate that the protective action of LTG could be mediated by interfering with phenytoin-induced impairment of calcium entry (Lacinova, 2005) (low intracellular calcium levels have been shown to contribute to neonatal neuronal apoptosis; Lema Tomé et al., 2006a; Turner et al., 2007). At higher doses of LTG, the inhibition of sodium channels may exacerbate the similar action of phenytoin, further suppressing neuronal activity and stimulating cell death.

Although the spectrum of clinical consequences of AED-induced neuronal apoptosis remains to be elucidated, our observation that LTG alone does not exhibit neonatal neuronal toxicity serves as an argument in favor of monotherapy during pregnancy and in neonates. Moreover, from the data presented here, the combination of LTG with phenytoin is preferable to a combination with phenobarbital, in terms of developmental neurotoxicity. Our findings also underscore the need for testing a range of doses of a given drug in combination with a variety of different drugs before making a conclusion regarding the relative risk for developmental neurotoxicity for the given AED.

	Acknowledgements

 
We thank Susanna Tsukerman for technical assistance.

	Footnotes

 
This study was supported by the research grant from GlaxoSmithKline, Epilepsy Foundation and National Institutes of Health Grants MH02040 and HD047890.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.107.123133.

ABBREVIATIONS: AED, antiepileptic drug; NMDA, N-methyl-D-aspartate; MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate; LTG, lamotrigine; PD, postnatal day; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; ANOVA, analysis of variance; VEH, vehicle.

Address correspondence to: Dr. Alexei Kondratyev, Georgetown University, W208 Research Bldg., 3970 Reservoir Rd., N.W., Washington, DC 20057. E-mail: kondrata{at}georgetown.edu

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This Article Abstract Full Text (PDF) All Versions of this Article: jpet.107.123133v1 322/2/494    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Katz, I. Articles by Kondratyev, A. Search for Related Content PubMed PubMed Citation Articles by Katz, I. Articles by Kondratyev, A.