The enigma of fetal alcohol neurotoxicity.
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 GABA(A) 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).
Olney
John W
JW
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. olneyj@psychiatry.wustl.edu
Wozniak
David F
DF
Farber
Nuri B
NB
Jevtovic-Todorovic
Vesna
V
Bittigau
Petra
P
Ikonomidou
Chrysanthy
C
D020268:Alcohol-Induced Disorders, Nervous System / Q000196:embryology; D000435:Alcoholic Intoxication / Q000151:congenital; D000818:Animals; D017209:Apoptosis; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000196:embryology / Q000378:metabolism; D006801:Humans; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism
D002492:Central Nervous System Depressants; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol