PMID- 17483293
OWN - NLM
STAT- MEDLINE
DCOM- 20070920
LR  - 20181201
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 322
IP  - 2
DP  - 2007 Aug
TI  - Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or 
      phenytoin on cell death in the neonatal rat brain.
PG  - 494-500
AB  - 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.
FAU - Katz, Irina
AU  - Katz I
AD  - Departments of Pediatrics, Georgetown University, Washington, DC 20057, USA.
FAU - Kim, Jinsook
AU  - Kim J
FAU - Gale, Karen
AU  - Gale K
FAU - Kondratyev, Alexei
AU  - Kondratyev A
LA  - eng
GR  - D047890/PHS HHS/United States
GR  - MH02040/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070504
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Anticonvulsants)
RN  - 0 (Triazines)
RN  - 6158TKW0C5 (Phenytoin)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
RN  - U3H27498KS (Lamotrigine)
RN  - YQE403BP4D (Phenobarbital)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Anticonvulsants/adverse effects/pharmacology
MH  - Apoptosis/*drug effects
MH  - Brain/*drug effects/pathology
MH  - Cerebral Cortex/drug effects/pathology
MH  - Corpus Striatum/drug effects/pathology
MH  - Dizocilpine Maleate/*pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Female
MH  - Lamotrigine
MH  - Male
MH  - Phenobarbital/*pharmacology
MH  - Phenytoin/*pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sex Factors
MH  - Thalamus/drug effects/pathology
MH  - Triazines/*pharmacology
EDAT- 2007/05/08 09:00
MHDA- 2007/09/21 09:00
CRDT- 2007/05/08 09:00
PHST- 2007/05/08 09:00 [pubmed]
PHST- 2007/09/21 09:00 [medline]
PHST- 2007/05/08 09:00 [entrez]
AID - jpet.107.123133 [pii]
AID - 10.1124/jpet.107.123133 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2007 Aug;322(2):494-500. doi: 10.1124/jpet.107.123133. Epub 
      2007 May 4.