Long‐term antiepileptic drug administration during early life inhibits hippocampal neurogenesis in the developing brain

Abstract

Certain antiepileptic drugs (AEDs) that are commonly used to treat seizures in children also affect cognition, and these effects can persist into adulthood, long after drug withdrawal. Widespread enhancement of apoptosis may be one mechanism underlying these lasting cognitive changes. Whether AEDs affect other processes in brain development during early postnatal life has not, however, been systematically analyzed. Here we determined whether chronic administration of common AEDs during early life alters cell proliferation and neurogenesis in the hippocampus. Postnatal day 7 (P7) rats received phenobarbital, clonazepam, carbamazepine, valproate, topiramate, or vehicle for 28 days. Bromodeoxyuridine was administered on P34 to label dividing cells. Cell proliferation was assessed 24 hr later, and cell survival and differentiation were assessed 28 days later. Phenobarbital and clonazepam significantly inhibited cell proliferation by 63% and 59%, respectively, and doublecortin immunoreactivity (indicator of neurogenesis) in the dorsal hippocampus was also significantly decreased by 26% and 24%, respectively. Survival of new cells steadily decreased in phenobarbital and clonazepam groups over 28 days. Reduced cell proliferation and survival resulted in fewer new neurons in the dentate gyrus, as confirmed by neuronal counting on P62. There were, however, no differences in cell distribution pattern or differentiation toward neuron and glial cells when phenobarbital and clonazepam groups were compared with controls. There were no changes in rats exposed to carbamazepine, valproate, or topiramate. Thus, inhibiting cell proliferation, survival, and neurogenesis in the developing hippocampus may be another potential mechanism underlying brain impairment associated with certain AED therapies in early life.

Different effects of high- and low-dose phenobarbital on post-stroke seizure suppression and recovery in immature CD1 mice

“…Stefovska et al (Stefovska et al, 2008) reported a decrease in neurogenesis in the subgranular zone after 3 doses of phenobarbital in the neonatal rat. Chen et al (Chen et al, 2009) corroborated these decreases in hippocampal neurogenesis after chronic administration to neonatal rats, and also reported a conservation of the relative proportions of newborn neuronal and glial cell types. It is possible that these are model-dependent differences: the experiments cited previously were performed in naïve rodents, while our ischemia model has already demonstrated suppressed neurogenesis in the DG after the stroke event (Kadam et al, 2008; Kadam et al, 2009a).…”

Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research

“…Other groups have also shown that brief exposure (P7–P8) to higher doses of phenobarbital (75 mg/kg) led to decreased neuronal number in the thalamus, striatum, frontal cortex, and hippocampus of rodents [171,210,224]. In addition, phenobarbital exposure from P7–P34 leads to a decrease in hippocampal progenitor cell proliferation, decreased expression of a marker of immature cells, and decreased survival of postnatally generated neurons in the adolescent animal [225,226], suggesting that drug exposure affects postnatal neurogenesis in the hippocampus. Rats exposed to phenobarbital during the first three weeks of life also have impaired development of olfactory bulb (∼25% reduction in medial olfactory bulb volume), with the greatest reductions in neuronal number in the external layers (mitral and glomerular neurons) and significant but more modest effects on the granule cell layer [227].…”

Benzodiazepines and the potential trophic effect of antidepressants on dentate gyrus cells in mood disorders

“…Type-2 progenitors in adult hippocampus express GABA A receptors that can be activated by synaptic stimuli and stimulate differentiation (Deisseroth and Malenka, 2005; Wang et al, 2005). Antiepileptic drugs, such as the barbiturate phenobarbital, which also act on the GABAergic system by binding to GABA A receptors (Rudolph et al, 1999), decrease neurogenesis by about 60% in the DG (Chen et al, 2009) and have cognitive effects that persist after drug cessation (Chen et al, 2009). Alcohol, which, like BZDs, modulates GABA A receptors to induce sedation (Laukkanen et al, 2013), decreases DG neurogenesis by up to 50% in adult rats after long-term exposure (Jang et al, 2002; Nixon and Crews, 2002; Rice et al, 2004).…”

“…Increased GABA activation via GABA A receptor agonists, such as BZD, appears to cause neuronal apoptosis in the developing brain of rodents (Chen et al, 2009). We found that mature granule neuron were fewer in subjects co-treated with BZD compared with subjects treated with antidepressant alone, and in BZD co-treated MD were comparable to untreated MD.…”