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Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain

机译:单独使用拉莫三嗪或与MK-801,苯巴比妥或苯妥英钠合用对新生大鼠脑细胞死亡的影响

摘要

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.
机译:新生大鼠的大脑易受抗癫痫药(AED)诱导的神经元凋亡的影响,尤其是与抗癫痫药联合使用时。这项研究评估了拉莫三嗪单独使用或与苯巴比妥,苯妥英钠或谷氨酸拮抗剂(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸氢结合(MK -801)在发育中的大鼠大脑中具有促凋亡作用。急性药物治疗后24小时,通过末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)分析评估大鼠幼崽(出生后第8天)的大脑区域(纹状体,丘脑和皮层区域)的细胞死亡。当剂量高达50 mg / kg时,单独使用Lamotrigine并不会增加神经元凋亡。 100 mg / kg后,细胞死亡显着增加。与单独使用MK-801或苯巴比妥治疗相比,将20 mg / kg拉莫三嗪与0.5 mg / kg MK-801或75 mg / kg苯巴比妥联合使用可使TUNEL阳性细胞显着增加。 30 mg / kg拉莫三嗪后苯妥英钠诱导的细胞死亡发生了类似的增强。相反,20 mg / kg拉莫三嗪可显着降低苯妥英钠诱导的细胞死亡。 10 mg / kg的拉莫三嗪对苯妥英钠诱导的细胞凋亡没有影响。尽管AED诱导的发育性神经元凋亡的功能和临床意义尚待阐明,但我们的发现仅单用拉莫三嗪就没有这种作用,因此该药物作为单一疗法对孕妇,早产儿或新生儿的治疗具有吸引力。但是,由于AED通常作为附加药物引入,因此在将Lamotrigine用于多药治疗时,可能需要仔细选择药物组合和剂量,以避免发育中的神经毒性。

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