Modulation of androgen and estrogen receptor expression by antiepileptic drugs and steroids in hippocampus of patients with temporal lobe epilepsy
| Autor: | Ralf Peter Meyer, Benedikt Volk, Philipp Capetian, Marcel Gehlhaus, Georgios Pantazis, Nina Killer, Rolf Knoth, Monika Hock |
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| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Estrogen receptor Hippocampus Pharmacology Lamotrigine Epilepsy Mice Sex Factors Cytochrome P-450 Enzyme System Internal medicine medicine Animals Cytochrome P-450 CYP3A Humans Cell Line Transformed Neurons Carbamazepine medicine.disease Androgen receptor Endocrinology Anticonvulsant Neurology Epilepsy Temporal Lobe Gene Expression Regulation Receptors Estrogen Receptors Androgen Phenobarbital Anticonvulsants Female Steroids Neurology (clinical) Psychology medicine.drug |
| Zdroj: | Epilepsia. 50(8) |
| ISSN: | 1528-1167 |
| Popis: | Purpose: Many of the antiepileptic drugs (AED)used in therapy of temporal lobe epilepsy(TLE) are known as cytochrome P450 (CYP,P450) inducers. These AEDs are thought tomodulate androgen and estrogen pathways inhippocampus, and therefore cause mental andreproductive disorders found in TLE patients.In the present study, we analyzed expression ofandrogen receptor (AR), estrogen receptor a(ERa), and CYP3A in the hippocampus of TLEpatients and in murine hippocampal cell lineHN25.1.Methods: Patients and cell lines had been treatedwith P450-inducing or noninducing AEDs, or withprednisolone, applied to prevent oedema forma-tion prior to neurosurgical resection of the epilep-tic hippocampus. Human patient samples wereanalyzed by immunohistochemical approach, theHN25.1 cell line by quantitative RT-PCR, CATreportergeneassay,andimmunoblot.Results: In both, humans and cell lines, the expres-sion of testosterone metabolising CYP3A4(human)orCYP3A11(mouse)andARwasup-reg-ulated when P450-inducing AEDs and/or predniso-lone had been applied. AR responsive CATreporter gene assay indicated an increase of AR-signalling after treatment of the HN25.1 cells withthe P450-inducers phenytoin and carbamazepine.ERa expression was increased only by the P450-inducing AEDs, but not by prednisolone, whichindicatesthat pathways differentfrom CYP3A4/11ledtoERaenhancement.Discussion:WeconcludethatP450-inducingAEDsinfluence AR expression and signalling in hippo-campus most likely via CYP3A4/11-induction. TheHN25.1 cell line holds promise to investigate thecorrelation between drug application and AR reg-ulation, and to specifically address issues that arerelevanttohumanTLEpatients.KEY WORDS: Androgen receptor, Antiepilepticdrug, Estrogen receptor a, Hippocampus,CytochromeP450,Temporallobeepilepsy.Epilepsy is a paroxysmal disorder of the brain, whichaffects about 1% of the population (Forsgren et al., 2005).Temporal lobe epilepsy, the most common form of thechronic intractable epilepsies, is correlated with 70%with the morphological sign of ammon’s horn sclerosis(AHS).AHSischaracterizedbydispersionanddamageofgranule cells of the dentate gyrus, neuronal loss mainly inthe CA1, CA3, and CA4 regions of the hippocampal for-mation, gliosis and microglial activation (Freiman et al.,2002).Initial choice of medication are the antiepileptic drugs(AEDs) carbamazepine, oxcarbazepine, lamotrigine, inspecial cases phenytoin and phenobarbital, whichusually act on ion-channels and the GABAergic-system(Rogawski & Loscher, 2004; Berkovic, 2005). Carba-mazepine, phenytoin, phenobarbital and oxcarbazepinehave the potency to induce cytochrome P450 (P450),mainly CYP3A and CYP2C isoforms, while lamotrigine |
| Databáze: | OpenAIRE |
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