Prenatal exposure to oxcarbazepine increases hippocampal apoptosis in rat offspring

Maciel, Angélica González; Rm, Romero-Velázquez; Alfaro-Rodríguez, Alfonso; Aparicio, Pedro Sánchez; Reynoso-Robles, Rafael

doi:10.1016/j.jchemneu.2019.101729

Cited by 8 publications

(8 citation statements)

References 138 publications

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“…OXC at a concentration of 281.25 mg/kg or more was seen to induce neurocyte apoptosis and brain damage by triggering Bax/Bcl-2 signaling pathway-mediated caspase 3 activation in neonatal rats [ 139 ]. An increase in hippocampal apoptosis was also observed in rat pups who were exposed to OXC prenatally [ 140 ]. However, no adverse effects related to the use of maternal OXC were found in a case study involving a pregnant individual and two children [ 58 ].…”

Section: Broad and Narrow Spectrum Anti-seizure Drugsmentioning

confidence: 99%

Elucidating the Potential Side Effects of Current Anti-Seizure Drugs for Epilepsy

Akyüz

Köklü

Ozenen

et al. 2021

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: Over the decades, various interventions have been developed and utilized to treat epilepsy. However, majority of epileptic patients are often first prescribed with anti-epileptic drugs (AED), now known as anti-seizure drugs (ASD), as a first line of defense to suppress their seizures and regain their quality of life. ASDs exert their anti-convulsant effects through various mechanisms of action including regulation of ion channels, blocking of glutamate-mediated stimulating neurotransmitter interaction, and enhancing the inhibitory GABA transmission. About one third of epileptic patients are often resistant to anti-convulsant drugs, while others develop numerous side effects which may lead to treatment discontinuation and further deterioration of quality of life. Common side effects of ASDs include headache, nausea and dizziness. However, more adverse effects such as auditory and visual problems, skin problems, liver dysfunction, pancreatitis and kidney disorders may also be witnessed. Some ASDs may even result in life-threatening conditions as well as serious abnormalities, especially in patients with comorbidities and in pregnant women. Nevertheless, some clinicians had observed a reduction in the development of side effects post individualized ASD treatment. This suggest that a careful and well-informed ASD recommendation to patients may be crucial for an effective and side-effect free control of their seizures. Therefore, this review aimed to elucidate the anticonvulsant effects of ASDs as well as their side effect profile, by discussing their mechanism of action and reported adverse effects based on clinical and preclinical studies, thereby providing clinicians with a greater understanding of the safety of current ASDs.

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Section: Broad and Narrow Spectrum Anti-seizure Drugsmentioning

confidence: 99%

Elucidating the Potential Side Effects of Current Anti-Seizure Drugs for Epilepsy

Akyüz

Köklü

Ozenen

et al. 2021

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“… ASM Model Administration Effect Ref Phenobarbital Sprague-Dawley rat offspring 40 mg/kg, i.p., from PND 7 3–4 weeks Decreases neurogenesis Reduction in BDNF and NT-3 mRNA expression [ 43 ] Human stem cells (TERA2.cl.SP12) 100–1000 μM Decreases neurogenesis Reduces viability and proportion of SC subsequently differentiated into neurons [ 42 ] Neonatal Wistar rats 50 mg/kg, i.p. throughout PND 4-6 Decreases neurogenesis Reduction in DCX + , calretinin + , NeuN + cells in the DG, Decreases the expression of Pax6, Sox2, Tbr1/2, Prox1, NGF, BDNF, NT-3 [ 57 ] Lacosamide C57BL/6J mice Hippocampus 10 mg/kg, i.p., 10 days Decreases neurogenesis Reduction in BrdU + /NeuN + cells in SGZ [ 47 ] C57BL/6J mice 10 mg/kg, i.p., 10 days Decreases neurogenesis Reduces NeuN + /BrdU + , GFAP + /NeuN + cells in the SGZ [ 48 ] Oxcarbazepine Wistar rat offspring Maternal exposure to 100 mg/kg, ED 7-15 Decreases neurogenesis Decreased DCX + cells in the SGZ [ 38 ] Wistar albino male rats Maternal exposure to 100 mg/kg, ED 1–5 or 6-15 Decreases neurogenesis [ 92 ] …”

Section: Discussionmentioning

confidence: 99%

“…It is hypothesized that neuronal apoptosis and alterations of neurogenesis are responsible for CBZ-induced cognitive deficits in the offsprings. A recent study by Gonzalez-Maciel showed that oral maternal exposure to 100 mg/kg/day of CBZ, before and during the neurogenesis period at embryonic days 7–15, increased neuronal apoptosis and decreased DCX + expressing immature neural cells in the SGZ of offsprings [ 38 ].…”

Section: The First-generation Asm and Neurogenesismentioning

confidence: 99%

“…Prenatal exposure to 100 mg/kg/day of OxCBZ, before and during the neurogenesis period at embryonic days 7–15, increased neuronal apoptosis and decreased DCX expressing immature neurons in the SGZ of rat offsprings [ 38 ]. Similarly, it was shown that OxCBZ (100 mg/kg) exposure during the preimplantation-implantation period (embryonic days 1–5) or organogenesis period (embryonic days 6–15) induced neuronal apoptosis in Wistar albino male rats [ 92 ].…”

Section: The Second- and Third-generations Asm And Neurogenesismentioning

confidence: 99%

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Differential effects of antiseizure medications on neurogenesis: Evidence from cells to animals

Alavi,

Al-Asady,

Fanoudi

et al. 2024

Heliyon

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“…Aberrations in the development of the fetal brain may increase risk of epilepsy . Given the alterations in fetal brain development experimentally induced by valproate and other ASMs in rodent models, it could be hypothesized that changes in neuron connectivity and excitability or from cytoarchitecture changes and/or migration abnormalities may lead to epileptogenic cortical areas . Previous work has suggested that children of mothers with epilepsy are at higher risk of developing epilepsy than are children of fathers with epilepsy, which has been coined the maternal effect .…”

Section: Introductionmentioning

confidence: 99%

Prenatal Exposure to Antiseizure Medications and Risk of Epilepsy in Children of Mothers With Epilepsy

Dreier,

Christensen,

Igland

et al. 2024

JAMA Netw Open

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ImportanceUse of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications for the child.ObjectiveTo examine whether use of valproate and other ASMs in pregnancy among mothers with epilepsy is associated with epilepsy risk in their children.Design, Setting, and ParticipantsThis prospective, population-based register cohort study included singletons born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Data analysis was performed from October 2022 to December 2023.ExposureRedeemed prescription for an ASM from 30 days before pregnancy until birth.Main Outcomes and MeasuresThe main outcome was epilepsy in children, assessed using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses from hospital care. Adjusted hazard ratios (AHRs) and 95% CIs were estimated using Cox proportional hazards regression. Secondary analyses included dose-response analyses, analyses using children of mothers who discontinued ASM prior to pregnancy as the reference, and sibling analyses.ResultsThis cohort study included 38 663 children of mothers with epilepsy (19 854 [51.4%] boys). Children were followed up from birth; the mean length of follow-up was 7.2 years (range 0-22 years). Compared with 22 207 children of mothers not using an ASM in pregnancy, increased risks of epilepsy in children of mothers who used valproate in pregnancy (monotherapy: AHR, 2.18; 95% CI, 1.70-2.79; polytherapy: AHR, 2.10; 95% CI, 1.49-2.96) were observed. However, there was no dose-dependent association, and there was a similar risk of epilepsy in siblings who were exposed and unexposed to valproate (AHR, 0.95; 95% CI, 0.50-1.82). Prenatal exposure to topiramate monotherapy was associated with increased risk of epilepsy (AHR, 2.32; 95% CI, 1.30-4.16), and the risk was greater for higher doses, but the risk attenuated in comparisons with children of mothers who discontinued topiramate before pregnancy (AHR, 1.19; 95% CI, 0.26-5.44). Prenatal exposure to clonazepam monotherapy was also associated with increased epilepsy risk (AHR, 1.90; 95% CI, 1.16-3.12), but limited follow-up and low numbers precluded further analyses. No associations were observed for prenatal exposure to lamotrigine (AHR, 1.18; 95% CI, 0.95-1.47), levetiracetam (AHR, 1.28; 95% CI, 0.77-2.14), carbamazepine (AHR, 1.13; 95% CI, 0.85-1.50), or oxcarbazepine (AHR, 0.68; 95% CI, 0.44-1.05).Conclusions and RelevanceIn this cohort study of children born to mothers with epilepsy, the associations found between prenatal exposure to certain ASMs and the child’s risk of epilepsy did not persist in sensitivity analyses, suggesting that maternal ASM use in pregnancy may not increase epilepsy risk in children beyond that associated with the maternal epilepsy itself. These findings are reassuring for women in need of treatment with ASM in pregnancy.

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Prenatal exposure to oxcarbazepine increases hippocampal apoptosis in rat offspring

Cited by 8 publications

References 138 publications

Elucidating the Potential Side Effects of Current Anti-Seizure Drugs for Epilepsy

Elucidating the Potential Side Effects of Current Anti-Seizure Drugs for Epilepsy

Differential effects of antiseizure medications on neurogenesis: Evidence from cells to animals

Prenatal Exposure to Antiseizure Medications and Risk of Epilepsy in Children of Mothers With Epilepsy

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