Brain pathology caused in the neonatal macaque by short and prolonged exposures to anticonvulsant drugs (original) (raw)

Fetal Exposure to GABA-Acting Antiepileptic Drugs Generates Hippocampal and Cortical Dysplasias

Epilepsia, 2007

Purpose: The management of epilepsy during pregnancy entails a number of concerns. While seizures may affect adversely maternal and fetal outcome, antiepileptic drugs (AEDs) may increase the incidence of congenital abnormalities and possibly affect postnatal cognitive development in the offspring. Experimental animal studies can aid in assessing teratogenic features associated with individual AEDs and/or with seizures, and to identify the mechanisms involved. The purpose of this study was to investigate the consequences of prenatal exposure to (a) different AEDs and (b) maternal seizures on brain maturational processes in rats.

Phenobarbital modifies seizure-related brain injury in the developing brain

Annals of Neurology, 1994

To investigate the potential role of drug therapy in preventing or exacerbating seizure-related brain injury in the prepubescent brain, we administered kainic acid to rats at postnatal day 35. Therapy with daily phenobarbital was started directly before or 1 day after kainic acid was administered, and was continued through postnatal day 153. Rats receiving phenobarbital had therapeutic concentrations during most of the 24-hour dosing period, but also experienced supratherapeutic peak concentrations. The animals were subsequently tested using the water maze (a measure of visuospatial memory), open field (a measure of activity level), and handling tests (a measure of emotionality). The frequency of spontaneous recurrent seizures was monitored during and after phenobarbital therapy. Kainic acid resulted in status epilepticus on postnatal day 35 in all the rats that received it but those receiving phenobarbital first manifested a shorter and less severe status epilepticus as compared to the rats given kainic acid alone. Rats starting phenobarbital immediately before kainic acid was administered did not differ from control rats on behavioral testing and had no subsequent spontaneous recurrent seizures and no histological lesions. Rats receiving kainic acid alone performed significantly poorer than did control rats in the water maze, were more aggressive, had histological lesions, and manifested spontaneous recurrent seizures. As compared to the group treated only with kainic acid, rats receiving kainic acid followed by phenobarbital at postnatal days 36 to 153 manifested similar aggressiveness and histological lesions, similar frequency of spontaneous recurrent seizures after phenobarbital taper, and even greater disturbances in memory, learning, and activity level. These results demonstrate that kainic acid–related injury can be prevented by a medication working through inhibitory mechanisms; that structural and functional damage in the prepubescent brain can be prevented through strategically timed pharmacotherapy; and that treatment of spontaneous recurrent seizures alone with daily exposure to phenobarbital does not decrease, and may actually exacerbate, damage in the kainic acid model.

Therapeutic strategies to avoid long-term adverse outcomes of neonatal antiepileptic drug exposure

Epilepsia, 2010

Antiepileptic drugs (AEDs) such as phenobarbital, phenytoin and valproic acid, when given in therapeutic doses to neonatal rats, cause pronounced neuronal apoptotic cell death. This effect is especially pronounced in the striatum and cortex during the second postnatal week; a period corresponding to the "brain growth spurt" (third trimester of gestation and early infancy) in humans. Of particular concern is the fact that phenobarbital is the most frequently used therapy for neonatal epilepsy. If AED-induced neuronal cell death leads to long-term functional impairment, then it becomes crucial to find therapies that avoid this neurotoxicity in the sensitive period. Here we examine short and long-term functional effects following exposure of neonatal rat pups to phenobarbital; the functions tested include striatal GABAergic synaptic responses and reflex development in pups, and fear conditioning, emotionality, and sensory-motor gating in adults. In all cases, phenobarbital exposure during the second postnatal week was sufficient to cause significant impairment. In contrast, adult animals exposed as pups to lamotrigine (given in a dose that does not cause apoptotic neuronal death) were not impaired on the tasks we examined. Our data suggest that treatments devoid of proapoptotic actions may be promising therapies for avoiding adverse outcomes after neonatal exposure. In addition, our findings identify early exposure to certain AEDs as an important potential risk factor contributing to psychiatric and neurological abnormalities later in life.

Neonatal phenobarbital exposure disrupts GABAergic synaptic maturation in rat CA1 neurons

Epilepsia, 2018

Phenobarbital is the most commonly utilized drug for the treatment of neonatal seizures. The use of phenobarbital continues despite growing evidence that it exerts suboptimal seizure control and is associated with long-term alterations in brain structure, function, and behavior. Alterations following neonatal phenobarbital exposure include acute induction of neuronal apoptosis, disruption of synaptic development in the striatum, and a host of behavioral deficits. These behavioral deficits include those in learning and memory mediated by the hippocampus. However, the synaptic changes caused by acute exposure to phenobarbital that lead to lasting effects on brain function and behavior remain understudied. Postnatal day (P)7 rat pups were treated with phenobarbital (75 mg/kg) or saline. On P13-14 or P29-37, acute slices were prepared and whole-cell patch-clamp recordings were made from CA1 pyramidal neurons. At P14 we found an increase in miniature inhibitory postsynaptic current (mIPS...

Antiepileptic drugs and apoptotic neurodegeneration in the developing brain

Proceedings of the National Academy of Sciences, 2002

Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. ␤-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy.

Neuronal deficits in mice following prenatal exposure to phenobarbital

Experimental Neurology, 1979

Pregnant mice (heterogeneous stock) were fed milled food containing 3 g/kg phenobarbital in the acid form (PhB) and water as their only nutritional source from gestation day 9 to 18, with smaller doses on gestation days 6 to 9 and 18 to parturition (B group). Control (C) females received milled food and water. Blood PhB concentrations of females and fetuses were between 40 and 2OO&ml blood. The brains of C and B male offspring were removed at age 50 days, fixed, sectioned, and stained with hematoxylin and eosin. Matching sagittal sections were selected for the study of the cerebellum, hippocampus, and the cerebral cortex. The brain weights of B offspring were 8% smaller than C offspring (P < 0.001). The area of the saggital section of the cerebellar and the hippcampal layers did not differ between groups. There were 30% fewer Purkinje cells in B offspring than in C offspring (P < 0.001). Consequently, their number per square millimeter was 26% smaller (P < 0.01). The number of the hippocamal pyramidal cells was 15% fewer in the B offspring (P < 0.02). There was no difference in the number of granule cells in both the cerebellum and hippocampus. The cerebral cortex was not affected by prenatal phenobarbital administration. The results suggest that the prenatally forming large neurons were affected by phenobarbital administration. However, there was no effect on the subsequent formation of the postnatally developing granule cells.

Antiepileptic Drugs and Apoptosis in the Developing Brain

Annals of the New York Academy of Sciences, 2003

A BSTRACT : Epilepsy is the most common neurologic disorder in young humans. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects by unknown mechanisms. We tested whether common AEDs cause neurodegeneration in the developing rat brain. Rats aged 3-30 days received phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, or valproic acid. Histologic examination of the brains revealed that these drugs cause widespread and dose-dependent apoptotic neurodegeneration in the developing rat brain during the brain growth spurt period. Apoptotic neurodegeneration was triggered at plasma drug levels relevant for seizure control in humans. Antiepileptic drugs lead to reduced expression of neurotrophins and decreased concentrations of the active forms of ERK1/2, RAF, and AKT. ␤-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorated AEDs-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with pre-or postnatal exposure of humans to antiepileptic therapy.