Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain
Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain
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DOI：
10.1124/jpet.107.123133
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Kondratyev, Alexei
中科院分区：
文献类型：
--
作者：
Katz, Irina;Kim, Jinsook;Kondratyev, Alexei
抗癫痫药物（AEDs），尤其是联合用药，可诱导新生大鼠脑神经元凋亡。本研究评价了拉莫三嗪单药或与苯巴比妥、苯妥英或谷氨酸拮抗剂（+）-5-甲基-10，11-二氢-5H-二苯并[a，d]环庚烯-5，10-亚胺马来酸氢盐（MK-801）联合给药对发育中大鼠脑的促凋亡作用。急性药物处理后24 h，通过末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）试验评估大鼠幼仔（出生后第8天）脑区（纹状体、丘脑和皮质区）的细胞死亡。拉莫三嗪单独给药时，剂量高达50 mg/kg时，神经元凋亡没有增加; 100 mg/kg后，细胞死亡显著增加。与MK-801或苯巴比妥单独给药相比，20 mg/kg拉莫三嗪与0.5 mg/kg MK-801或75 mg/kg苯巴比妥联合给药导致TUNEL阳性细胞显著增加。在30 mg/kg拉莫三嗪后，苯妥英诱导的细胞死亡也发生了类似的增强。相反，20 mg/kg拉莫三嗪显著减弱苯妥英诱导的细胞死亡。拉莫三嗪10 mg/kg对苯妥英诱导的细胞凋亡无影响。虽然AED诱导的发育神经元凋亡的功能和临床意义仍有待阐明，我们的发现，拉莫三嗪单独是缺乏这种效果，使这种药物作为单一治疗的妇女在怀孕期间，早产儿或新生儿有吸引力。然而，由于AED通常作为添加药物引入，当拉莫三嗪用于多药治疗时，可能需要仔细选择药物组合和剂量，以避免发育神经毒性。
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.