Seizures and Antiepileptic Drugs: Does Exposure Alter Normal Brain Development in Animal Models?

Galanopoulou, Aristea S.; Velı́šek, Libor; Moshé, Solomon L.

doi:10.1007/978-1-60761-287-2_6

Cited by 4 publications

(3 citation statements)

References 197 publications

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“…The complexity of the drug‐resistant phenotype reflects the nature of the pathophysiologic process, its possible evolution over time, and the different individual sensitivity to drugs (Loscher et al., 2009). In order to elucidate the mechanisms underlying this condition, a pharmacodynamic hypothesis and a pharmacokinetic hypothesis have been proposed (Dresser et al., 2000; Oby & Janigro, 2006; Galanopoulou et al., 2009; Granata et al., 2009). The latter hypothesis suggests that the bioavailability of drug in epileptic brain regions could be diminished by the overexpression of transporter proteins (e.g., MDR1) at the blood–brain barrier (BBB; Dombrowski et al., 2001; Marchi et al., 2004; Loscher & Potschka, 2005; Marchi et al., 2010).…”

mentioning

confidence: 99%

Cellular localization and functional significance of CYP3A4 in the human epileptic brain

Ghosh¹,

Marchi

Desai³

et al. 2011

Epilepsia

117

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SUMMARYPurpose: Compelling evidence supports the presence of P450 enzymes (CYPs) in the central nervous system (CNS). However, little information is available on the localization and function of CYPs in the drug-resistant epileptic brain. We have evaluated the pattern of expression of the specific enzyme CYP3A4 and studied its co-localization with MDR1. We also determined whether an association exists between CYP3A4 expression and cell survival. Methods: Brain specimens were obtained from eight patients undergoing resection to relieve drug-resistant seizures or to remove a cavernous angioma. Each specimen was partitioned for either immunostaining or primary culture of human endothelial cells and astrocytes. Immunostaining was performed using anti-CYP3A4, MDR1, GFAP, or NeuN antibodies. High performance liquid chromatography-ultraviolet (HPLC-UV) analysis was used to quantify carbamazepine (CBZ) metabolism by these cells.CYP3A4 expression was correlated to DAPI) condensation, a marker of cell viability. Human embryonic kidney (HEK) cells were transfected with 4¢,6-diamidino-2-phenylindole (CYP3A4 to further evaluate the link between CYP3A4 levels, CBZ metabolism, and cell viability. Key Findings: CYP3A4 was expressed by blood-brain barrier (BBB) endothelial cells and by the majority of neurons (75 ± 10%). Fluorescent immunostaining showed coexpression of CYP3A4 and MDR1 in endothelial cells and neurons. CYP3A4 expression inversely correlated with DAPI nuclear condensation. CYP3A4 overexpression in HEK cells conferred resistance to cytotoxic levels of carbamazepine. CYP3A4 levels positively correlated with the amount of CBZ metabolized. Significance: CYP3A4 brain expression is not only associated with drug metabolism but may also represent a cytoprotective mechanism. Coexpression of CYP3A4 and MDR1 may be involved in cell survival in the diseased brain.

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mentioning

confidence: 99%

Cellular localization and functional significance of CYP3A4 in the human epileptic brain

Ghosh¹,

Marchi

Desai³

et al. 2011

Epilepsia

117

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“…Epigenetic and societal factors, seizures and their treatments, as well as simple nonepileptogenic stressors or experiences may alter the natural course of epilepsy and epileptogenesis [63,64]. Genetic factors may further modify seizure and epilepsy outcomes, sometimes in unpredictable manners [65].…”

Section: What Are the Challenges?mentioning

confidence: 99%

In Search of Epilepsy Biomarkers in the Immature Brain: Goals, Challenges and Strategies

Galanopoulou¹,

Moshé

2011

Biomarkers Med.

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Epilepsy and seizures are very common in the early years of life and are often associated with significant morbidity and mortality. Identification of biomarkers for the early detection of epileptogenicity, epileptogenesis, comorbidities, disease progression and treatment implementation will be very important in implementing more effective therapies. This article summarizes the current needs in the search for new early life epilepsy-related biomarkers and discusses the candidate biomarkers that are under investigation, as well as the challenges associated with the identification and validation of these biomarkers.

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“…[46][47][48] Antiepileptic and anaesthetic drugs can induce apoptosis in the developing brain. [46][47][48] Antiepileptic and anaesthetic drugs can induce apoptosis in the developing brain.…”

Section: Anti-epileptic Drugs and Brain Morphologymentioning

confidence: 99%

Anti-Epileptic Drugs and Brain and Behavioural Development in Animal Models and Humans

O’Donoghue

2010

Fet. Matern. Med. Rev.

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Women with epilepsy constitute about 0.6% of pregnancies. The potential for major structural malformations following gestational exposure to anti-epileptic drugs (AEDs) is well known and causes concern as how best to manage epilepsy during pregnancy. In this review we focus on the structural and functional effects on the developing brain to complement other recent reviews. We do not cover neural tube defects which have been reviewed elsewhere. Suffice to say that carbamazepine, lamotrigine and, in particular, valproate exposure are associated with them. We discuss studies based on animal models as well as those that have followed-up children exposed to AEDs in-utero. Careful longitudinal human research can document the cognitive and behavioural effects, but the long time scales required and inability to rule out confounding variables, both genetic and environmental, are serious limitations. Animal studies are based on the assumption that many developmental processes are conserved between the animals used in the models (most often rodents) and humans. However, the hugely expanded cortex and cognitive and behavioural repertoire of humans implies that there are aspects that can not be well modelled. In addition, due to differences in how susceptible different species are to various teratogens, studies always need to be done in man as well. Nevertheless, an understanding of the molecular mechanisms of neuro-teratogenesis derived from animal models will help us predict which anti-epileptic drugs are likely to cause fewer neuro-developmental problems in humans.

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Seizures and Antiepileptic Drugs: Does Exposure Alter Normal Brain Development in Animal Models?

Cited by 4 publications

References 197 publications

Cellular localization and functional significance of CYP3A4 in the human epileptic brain

Cellular localization and functional significance of CYP3A4 in the human epileptic brain

In Search of Epilepsy Biomarkers in the Immature Brain: Goals, Challenges and Strategies

Anti-Epileptic Drugs and Brain and Behavioural Development in Animal Models and Humans

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