Abstract
Pregnant women with epilepsy have to balance maternal and fetal risks associated with uncontrolled seizures against the potential teratogenic effects from antiepileptic drugs (AEDs). Carbamazepine (CBZ) is among the four most commonly used AEDs for treatment of pregnant epileptic women. We previously reported that new-born children had a decreased head circumference after in utero CBZ exposure. This study investigates how prenatal exposure of CBZ influences the number of neurons in new-born and young mouse hippocampus, amygdala and cortex cerebri. Clinical studies describe inconclusive results on if prenatal CBZ treatment influences cognition. Here we investigate this issue in mice using two well characterized cognitive tasks, the passive avoidance test and the Morris water maze test. Prenatal exposure of CBZ reduced the number of neurons (NeuN-immunoreactive cells) in the new-born mouse hippocampus with 50% compared to non-exposed mice. A reduction of neurons (20%) in hippocampus was still observed when the animals were 5 weeks old. These mice also displayed a 25% reduction of neurons in cortex cerebri. Prenatal CBZ treatment did not significantly impair learning and memory measured in the passive avoidance test and in the Morris water maze. However, these mice displayed a higher degree of thigmotaxic behaviour than the control mice. The body weight of prenatally CBZ exposed five-week old mice were lower compared to control mice not exposed to CBZ (p = 0.001). In conclusion, prenatal exposure to CBZ reduces the number of neurons dramatically in areas important for cognition such as hippocampus and cortex, without severe impairments on learning and memory. These results are in line with some clinical studies, reporting that CBZ has minor negative effects on cognition. The challenge for future studies are to segment out what possible effects a reduction of neurons could have on different types of cognition, like intellectual ability and social interaction.
Highlights
Epilepsy affects 1–2% of humans worldwide and one third of those are women in reproductive age [1,2]
Prenatal CBZ exposure reduced the number of mature neurons (NeuN-immunoreactive cells) in the CA1 and CA3 regions of hippocampus (P = 0.0013, Fig. 1A) by 50% compared to the control group not exposed to CBZ
Prenatal CBZ exposure reduced the number of mature neurons in hippocampal CA1 and CA3 regions in 5 week-old mice, compared to non-exposed mice (P = 0.0004, Fig. 2A)
Summary
Epilepsy affects 1–2% of humans worldwide and one third of those are women in reproductive age [1,2]. Both seizures and antiepileptic drug (AED) treatment during pregnancy are thought to influence the child negatively. Pregnant women with epilepsy have to balance maternal and fetal risks associated with uncontrolled seizures against the potential teratogenic effects from AEDs. The most commonly used AEDs for treatment of pregnant epileptic women today are valproate (VPA), phenytoin (PHT), carbamazepine (CBZ) and lamotrigine (LTG) [9]. Pregnancy increases the risk for the onset and recurrence of several psychiatric disorders and pregnant women suffering from affective disorders do often require treatment with mood stabilizers (lithium carbonate, VPA, CBZ, LTG), antidepressants and/or antipsychotics [11,12]
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