Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development

Abstract

Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation) can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs) in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs) and anti-epileptics (AEDs), mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which alcohol, GAs and AEDs produce neurobehavioral deficit syndromes is by triggering apoptotic death and deletion of neurons and OLs (or their precursors) from the developing brain. Therefore, there is a need for research aimed at deciphering mechanisms by which these agents trip the apoptosis trigger, the ultimate goal being to learn how to prevent these agents from causing neurodevelopmental disabilities.

Safety and efficacy of chloral hydrate for procedural sedation in paediatric ophthalmology: a systematic review and meta-analysis

“…Anaesthetic agents are thought to exert toxic effects on brain development by either augmenting GABAergic function or by blocking NMDA glutamatergic function 44 45. CH is known to promote GABAergic activity46 and may affect neurocognitive development.…”

Hyperactivity and depression-like traits in Bax KO mice

“…Disruption of this complex and highly conserved process by endogenous or environmental factors can lead to a wide range of deficits (Creeley and Olney, 2013; McCann and Soriano, 2012). For instance, abnormally high rates of cell death are observed in Down syndrome, bipolar disorder, and mood disorders such as depression (Berk et al, 2014; Busciglio and Yankner, 1995; Garcia-Fuster et al, 2014; Uribe and Wix, 2012; Wisniewski and Kida, 1994).…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…Several experimental studies dealing with postnatal administration of NMDA receptor antagonists such as MK-801, ketamine or ethanol have shown a devastating cell apoptotic degeneration in several brain regions of animals models, resulting in learning deficits (reviewed in Fredriksson and Archer, 2004;Creeley and Olney, 2013). The apoptosis induced in developing brain after exposure to NMDA receptor antagonists is not reversible although the developing brain has plasticity properties that may allow to a certain degree to compensate for neuronal losses.…”

“…The apoptosis induced in developing brain after exposure to NMDA receptor antagonists is not reversible although the developing brain has plasticity properties that may allow to a certain degree to compensate for neuronal losses. This severe bilaterally symmetrical neuronal losses in both hemispheres that occurs by treatment with NMDA receptor antagonists leads to neurobehavioral disorders including learning and memory deficits (Creeley and Olney, 2013).…”