TY - JOUR
T1 - The enigma of fetal alcohol neurotoxicity
AU - Olney, John W.
AU - Wozniak, David F.
AU - Farber, Nuri B.
AU - Jevtovic-Todorovic, Vesna
AU - Bittigau, Petra
AU - Ikonomidou, Chrysanthy
N1 - Funding Information:
Supported in part by NIA grant AG 1135, NID5A grant DA 0507, 2 NEI grant EY 08089, NICHD grant HD 371 0 (Merit award to JWO), NARSAD 2000 Toulmn DistiinguisdhInvestiegatr oAward (JWO), NIDA Scientist Developmnt Aewrs dfaorClinicians D0020 (NBF9) and DA DA0046 (V0JT) and DFG grant Ik2/2-1 (CI).
PY - 2002
Y1 - 2002
N2 - The neurotoxic effects of ethanol on the human fetal brain (fetal alcohol syndrome, FAS) have been recognized for three decades, but the underlying mechanisms have remained elusive. Recently, we discovered that a single episode of ethanol intoxication lasting for several hours can trigger a massive wave of apoptotic neurodegeneration in the developing rat or mouse brain. The window of vulnerability coincides with the developmental period of synaptogenesis, also known as the brain growth-spurt period, which in rodents is a postnatal event, but in humans extends from the sixth month of gestation to several years after birth. We propose that the N-methyl-D-aspartate (NMDA) antagonist and gamma-aminobutyric (GABA)mimetic properties of ethanol are responsible for its apoptogenic action, in that we have found that other drugs that block NMDA glutamate receptors or mimic GABA at GABAA receptors also trigger apoptotic neurodegeneration in the developing brain. Our findings have clinical significance, not only because they can explain the reduced brain mass and neurobehavioral disturbances associated with the human FAS, but because many agents in the human environment, other than ethanol, have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers [phencyclidine (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines], and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).
AB - The neurotoxic effects of ethanol on the human fetal brain (fetal alcohol syndrome, FAS) have been recognized for three decades, but the underlying mechanisms have remained elusive. Recently, we discovered that a single episode of ethanol intoxication lasting for several hours can trigger a massive wave of apoptotic neurodegeneration in the developing rat or mouse brain. The window of vulnerability coincides with the developmental period of synaptogenesis, also known as the brain growth-spurt period, which in rodents is a postnatal event, but in humans extends from the sixth month of gestation to several years after birth. We propose that the N-methyl-D-aspartate (NMDA) antagonist and gamma-aminobutyric (GABA)mimetic properties of ethanol are responsible for its apoptogenic action, in that we have found that other drugs that block NMDA glutamate receptors or mimic GABA at GABAA receptors also trigger apoptotic neurodegeneration in the developing brain. Our findings have clinical significance, not only because they can explain the reduced brain mass and neurobehavioral disturbances associated with the human FAS, but because many agents in the human environment, other than ethanol, have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers [phencyclidine (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines], and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).
KW - Alcohol
KW - Apoptosis
KW - Ethanol
KW - Fetal alcohol syndrome
KW - GABA
KW - Glutamate
KW - Neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=0036260254&partnerID=8YFLogxK
U2 - 10.1080/07853890252953509
DO - 10.1080/07853890252953509
M3 - Review article
C2 - 12108574
AN - SCOPUS:0036260254
SN - 0785-3890
VL - 34
SP - 109
EP - 119
JO - Annals of Medicine
JF - Annals of Medicine
IS - 2
ER -