Abstract
Glutamate (Glu) and γ-aminobutyric acid (GABA) are major neurotransmitters in the mammalian brain which regulate brain development at molecular, cellular, and systems level. Sedative, anesthetic, and antiepileptic drugs (AEDs) interact with glutamate and GABA receptors to produce their desired effects. The question is posed whether such interference with glutamatergic and GABAergic neurotransmission may exert undesired, and perhaps even detrimental effects on human brain development. Preclinical research in rodents and non-human primates has provided extensive evidence that sedative, anesthetic, and AEDs can trigger suicide of neurons and oligodendroglia, suppress neurogenesis, and inhibit normal synapse development and sculpting. Behavioral correlates in rodents and non-human primates consist of long-lasting cognitive impairment. Retrospective clinical studies in humans exposed to anesthetics or AEDs in utero, during infancy or early childhood have delivered conflicting but concerning results in terms of a correlation between drug exposure and impaired neurodevelopmental outcomes. Prospective studies are currently ongoing. This review provides a short overview of the current state of knowledge on this topic.
Highlights
Short- and long-term deleterious effects, resulting from any interference with normal brain development, differ depending on the nature of interference, and the timing of the insult (Rodier, 1980)
In the central nervous system, structures are built by cell proliferation, migration, and a sequence of steps called differentiation
At the age of 6 months, phenobarbital-treated rats had fewer neurons in the dentate gyrus and performed worse than saline-treated littermates in water maze learning and memory task. These findings show that blockade of NMDA receptor-mediated excitation, as well as enhancement of GABAA-receptor activation, impair cell proliferation, and inhibit neurogenesis in the immature rat brain (Stefovska et al, 2008)
Summary
Short- and long-term deleterious effects, resulting from any interference with normal brain development, differ depending on the nature of interference, and the timing of the insult (Rodier, 1980). Any compound that interferes with these processes may trigger apoptotic degeneration of neurons that would not have otherwise been deleted from the developing brain, or may promote survival of unnecessary cells (Webb et al, 2001). NMDA receptors undergo a period of hypersensitivity through increased expression of specific receptor subunits (McDonald et al, 1988; Ikonomidou et al, 1989; Miyamoto et al, 2001) During this period, which extends from late fetal life to the first 2 weeks after birth in the rat, blockade of NMDA receptors with dizocilpine [(+)MK801], phencyclidine, ketamine, or 3-((6)-2carboxypiperazin-4-yl)propyl-1-phosphonate (CPP) for a period of hours triggers widespread apoptotic neurodegeneration in the brain (Ikonomidou et al, 1999) and may lead to detrimental longterm effects (Behar et al, 1999; Popke et al, 2001). Treatment of infant rats with intraperitoneal injections of (+)MK801 resulted in a marked increase of degenerating neurons from threefold in the hypothalamus to 39-fold in the laterodorsal thalamus, when examined at 24 h by appropriate staining techniques
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