Environmental Agents That Have the Potential to Trigger Massive Apoptotic Neurodegeneration in the Developing Brain

Abstract

We review recent findings pertaining to several environmental agents (ethanol, phencyclidine, ketamine, nitrous oxide, barbiturates, benzodiazepines, halothane, isoflurane, and propofol) that have the potential to delete large numbers of neurons from the developing brain by a newly discovered mechanism involving interference in the action of neurotransmitters [glutamate and y-amino butyric acid (GABA) at Nmethyl-D-aspartate (NMDA)1 and GABAA receptors during the synaptogenesis period, also known as the brain growth-spurt period. Transient interference (lasting > 4 hr) in the activity of these transmitters during the synaptogenesis period (the last trimester of pregnancy and the first several years after birth in humans) causes millions of developing neurons to commit suicide (die by apoptosis). Many of these agents are drugs of abuse (ethanol is a prime example) to which the human fetal brain may be exposed during the third trimester by drug-abusing mothers. Ethanol triggers massive apoptotic neurodegeneration in the developing brain by interfering with both the NMDA and GABAA receptor systems, and this can explain the reduced brain mass and lifelong neurobehavioral disturbances associated with intrauterine exposure of the human fetus to ethanol (fetal alcohol syndrome). Exposure of the immature brain in a medical treatment context is also of concern because many of these agents are drugs used frequently as sedatives, tranquilizers, anticonvulsants, or anesthetics in pediatric and/or obstetrical medicine. Because this is a newly discovered mechanism, further research will be required to fully ascertain the nature and degree of risk posed by exposure of the developing human brain to environmental agents that act by this mechanism.

Personality disorder in adolescence

“…However, the full and longterm extent of the effects of psycho active substances on forming and developing neural networks, especially in the prefrontal cortex, is not yet known. It is possible that ethanol, in particular, may be neurotoxic to processes such as synaptogenesis or dendritisation, and makes the adolescent brain increasingly vulnerable to environmental challenges that in turn may make adult psychiatric disturbance more likely (Olney 2000).…”

Selective inhibition of γ-aminobutyric acid type A receptors in human IMR-32 cells by low concentrations of toluene

“…respect, it is interesting to note that the hypothesis that neuronal degeneration may relate to the potential of agents to disturb the balance of excitation and inhibition in interrelated glutamatergic and GABA-ergic pathways in the central nervous system (Olney et al, 2000) is beginning to find support from experimental evidence.…”

Recommended Neuroanatomical Sampling Practices for Comprehensive Brain Evaluation in Nonclinical Safety Studies

“…10. MK-801 (also known as dizocilpine): retrosplenial cortex; dentate gyrus; piriform cortex; tenia tecta; amygdala; entorhinal cortex (Creeley, Wozniak, Nardi et al 2006;Creeley, Wozniak, Labruyere et al 2006;Ellison 1995;Fix et al 1996;Fix et al 1993;Fix et al 1994;Fix et al 1995;Horvath et al 1997;Maas et al 2005;Olney 2003;Olney et al 2004;Olney et al 2000;Olney et al 1987;Olney, Ikonomidou et al 1989;Olney, Labruyere et al 1989;Jevtovic-Todorovic, Hartman et al 2003;Jevtovic-Todorovic, Beals et al 2003;Jevtovic-Todorovic et al 2000;Wozniak et al 1998). 11.…”