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Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain - PubMed

Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain

Patrick A Forcelli et al. Epilepsia. 2011 Dec.

Abstract

The induction of neuronal apoptosis throughout many regions of the developing rat brain by phenobarbital and phenytoin, two drugs commonly used for the treatment of neonatal seizures, has been well documented. However, several limbic regions have not been included in previous analyses. Because drug-induced damage to limbic brain regions in infancy could contribute to emotional and psychiatric sequelae, it is critical to determine the extent to which these regions are vulnerable to developmental neurotoxicity. To evaluate the impact of antiepileptic drug (AED) exposure on limbic nuclei, we treated postnatal day 7 rat pups with phenobarbital, phenytoin, carbamazepine, or vehicle, and examined nucleus accumbens, septum, amygdala, piriform cortex, and frontal cortex for cell death. Histologic sections were processed using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay to label apoptotic cells. Nucleus accumbens displayed the highest level of baseline cell death (vehicle group), as well as the greatest net increase in cell death following phenobarbital or phenytoin. Phenobarbital exposure resulted in a significant increase in cell death in all brain regions, whereas phenytoin exposure increased cell death only in the nucleus accumbens. Carbamazepine was without effect on cell death in any brain region analyzed, suggesting that the neurotoxicity observed is not an inherent feature of AED action. Our findings demonstrate pronounced cell death in several important regions of the rat limbic system following neonatal administration of phenobarbital, the first-line treatment for neonatal seizures in humans. These findings raise the possibility that AED exposure in infancy may contribute to adverse neuropsychiatric outcomes later in life.

Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

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Conflict of interest statement

Disclosure of Conflicts of Interest:

None of the authors has any conflict of interest to disclose. “We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.”

Figures

Figure 1
Figure 1

Representative photomicrographs of TUNEL-stained sections for each brain region from animals treated with: vehicle (control) (a, e, i, m, q), phenobarbital (b, f, j, n, r), phenytoin (c, g, k, o, s), and carbamazepine (d, h, l, p, t). Dotted lines illustrate anatomical boundaries. TUNEL positive cells are stained brown. Scale bar = 250µm. AC = anterior commissure, LV = lateral ventricle, Ce = Central amygdala, BL = basal and lateral amygdala, EC = external capsule, Roman numerals I to IV = cortical layers one to five. See Figure 2 for schematic representations of brain regions.

Figure 2
Figure 2

Quantification of cell death. (a) Baseline levels of cell death following vehicle (control). (b) Net increase (over baseline cell death, as presented in Figure 2a) for each brain area and drug treatment. * = significantly different than baseline levels of cell death, P<0.05. Schematics are modified from the atlas of Sherwood and Timiras (1970). Photomicrograph (10x) of nucleus accumbens with the inset showing TUNEL-positive cells (40x, indicated by white arrowhead).

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References

    1. Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, Dzietko M, Pesditschek S, Mai I, Dikranian K, Olney JW, Ikonomidou C. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A. 2002;99:15089–15094. - PMC - PubMed
    1. Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, Dissen GA, Creeley CE, Olney JW. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112:834–841. - PMC - PubMed
    1. Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979;3:79–83. - PubMed
    1. Farber NB, Creeley CE, Olney JW. Alcohol-induced neuroapoptosis in the fetal macaque brain. Neurobiol. Dis. 2010;40:200–206. - PMC - PubMed
    1. Forcelli PA, Janssen MJ, Stamps LA, Sweeney C, Vicini S, Gale K. Therapeutic strategies to avoid long-term adverse outcomes of neonatal antiepileptic drug exposure. Epilepsia. 2010;51 Suppl 3:18–23. - PMC - PubMed

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