Neuropathological Sequelae of Developmental Exposure to Antiepileptic and Anesthetic Drugs

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.

An evaluation of a human stem cell line to identify risk of developmental neurotoxicity with antiepileptic drugs

“…Carbamazepine and lamotrigine are considered the least neurotoxic AEDs to the developing brain amongst the major anticonvulsants (Turski and Ikonomidou, 2012;Verrotti et al, 2014). Our analysis indicated that lamotrigine had little or no impact on cell cycle but it did reduce cell viability, possibly via increased necrosis, and the proportion of neurons derived at 15 days differentiation.…”

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

“…Epileptic encephalopathies (Landau‐Kleffner syndrome, continuous spike wave in slow wave sleep) may respond to hormonal therapy, whereas seizures in Dravet syndrome can be exacerbated by sodium channel blockers 20, 21, 22, 23. The neurobiology of the very young brain is very different from that in older age groups; consequently, age‐ and sex‐specific effects, efficacy, and tolerability of tested drugs cannot be predicted by the effects in older subjects 24, 25, 26. There are also age‐ and sex‐specific mechanisms involved in ictogenesis or epileptogenesis of early life seizures and epilepsies involving different underlying pathologies, network functions, intracellular and neuronal signaling, and communication patterns that are peculiar to certain stages of the disease or developmental stages 24, 25, 27…”

Recent Advances in the Pharmacotherapy of Infantile Spasms

“…Open questions still remain: can the relapses be avoided with prolonged corticosteroid or vigabatrin treatment, or will prolonged treatment cause glucocorticoid-induced dementia [36] or vigabatrin-induced visual field defects and apoptosis in the brain [37,38]. It is known that glucocorticoid stimulation induced by mild stress has positive effects on the hippocampus, but severe stress induces apoptosis, which would favour the use of small doses of corticosteroids or ACTH.…”

“…Drugs such as vigabatrin that increase synaptic concentrations of GABA in the brain can, in animals, cause apoptotic degeneration in the developing brain, but not after brain development has been completed [37,38].…”