Neurotransmitters and apoptosis in the developing brain.
In the immature mammalian brain during a period of rapid growth (brain growth spurt/synaptogenesis period), neuronal apoptosis can be triggered by the transient blockade of glutamate N-methyl-d-aspartate (NMDA) receptors, or the excessive activation of gamma-aminobutyric acid (GABA(A)) receptors. Apoptogenic agents include anesthetics (ketamine, nitrous oxide, isoflurane, propofol, halothane), anticonvulsants (benzodiazepines, barbiturates), and drugs of abuse (phencyclidine, ketamine, ethanol). In humans, the brain growth spurt period starts in the sixth month of pregnancy and extends to the third year after birth. Ethanol, which has both NMDA antagonist and GABA(A) agonist properties, is particularly effective in triggering widespread apoptotic neurodegeneration during this vulnerable period. Thus, maternal ingestion of ethanol during the third trimester of pregnancy can readily explain the dysmorphogenic changes in the fetal brain and consequent neurobehavioral disturbances that characterize the human fetal alcohol syndrome. In addition, there is basis for concern that agents used in pediatric and obstetrical medicine for purposes of sedation, anesthesia, and seizure management may cause apoptotic neuronal death in the developing human brain.
Ikonomidou
C
C
Department of Pediatric Neurology, Charité, Virchow Clinics, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany. hrissanthi.ikonomidou@charite.de
Bittigau
P
P
Koch
C
C
Genz
K
K
Hoerster
F
F
Felderhoff-Mueser
U
U
Tenkova
T
T
Dikranian
K
K
Olney
J W
JW
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D006801:Humans; D016202:N-Methylaspartate / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000502:physiology*
D018682:GABA Agents; D018377:Neurotransmitter Agents; D000431:Ethanol; D016202:N-Methylaspartate