Modulation of androgen and estrogen receptor expression by antiepileptic drugs and steroids in hippocampus of patients with temporal lobe epilepsy

Abstract

Summary 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 to modulate androgen and estrogen pathways in hippocampus, and therefore cause mental and reproductive disorders found in TLE patients. In the present study, we analyzed expression of androgen receptor (AR), estrogen receptor α (ERα), and CYP3A in the hippocampus of TLE patients and in murine hippocampal cell line HN25.1. Methods: Patients and cell lines had been treated with P450‐inducing or noninducing AEDs, or with prednisolone, applied to prevent oedema formation prior to neurosurgical resection of the epileptic hippocampus. Human patient samples were analyzed by immunohistochemical approach, the HN25.1 cell line by quantitative RT‐PCR, CAT reporter gene assay, and immunoblot. Results: In both, humans and cell lines, the expression of testosterone metabolising CYP3A4 (human) or CYP3A11 (mouse) and AR was up‐regulated when P450‐inducing AEDs and/or prednisolone had been applied. AR responsive CAT reporter gene assay indicated an increase of AR‐signalling after treatment of the HN25.1 cells with the P450‐inducers phenytoin and carbamazepine. ERα expression was increased only by the P450‐inducing AEDs, but not by prednisolone, which indicates that pathways different from CYP3A4/11 led to ERα enhancement. Discussion: We conclude that P450‐inducing AEDs influence AR expression and signalling in hippocampus most likely via CYP3A4/11‐induction. The HN25.1 cell line holds promise to investigate the correlation between drug application and AR regulation, and to specifically address issues that are relevant to human TLE patients.

Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERα)

“…In most tissues, endogenous ER expression is controlled by the abundance of estrogen; ER expression is low in the presence of lower estrogen levels and high when estrogen is high (44,45). For example, treatment of temporal lobe epilepsy patients with P450-inducing anti-epileptic drugs (phenytoin and carbamazepine) increased the level of E2 in patients causing a significant upregulation of ERα mRNA and proteins in their hippocampal pyramidal neurons (46,47). Here, we show that wild-type PCDH19 associates with NONO and, directly or indirectly, affects ERα-mediated gene expression, which is further enhanced in the presence of E2.…”

Cytochrome P450 enzymes in the brain: emerging evidence of biological significance

“…Anti-epileptic drug s such as oxcarbazepine, carbamazepine and phenytoin are potent inducers of CYP3A4 in human hippocampal pyramidal neurons [32]. CYP3A4 metabolizes testosterone and estradiol [33, 34], both of which are neuroactive steroids that can influence mood, behavior, sexuality, memory and cognition [35].…”

Pathophysiological implications of neurovascular P450 in brain disorders

“…AEDs could be locally metabolized, resulting in the loss of therapeutic efficacy or production of neurotoxic molecules [20]. AEDs, such as oxcarbazepine, carbamazepine, and phenytoin, are associated with CYP3A4 in human hippocampal pyramidal neurons [68]. As a result, induction of CYP3A4 metabolism in the brain can alter brain function.…”

“…In addition, earlier studies showed CYP3A4 expression (in protein and mRNA) to be significantly elevated in epileptic brain endothelial cells, isolated from brain resections of DRE, when compared with commercially procured, control brain endothelial cells [7,8]. Patients treated with AED have higher expression of both androgen receptors and CYP3A4 in the hippocampus compared with patients with untreated epilepsy [68]. Similarly, administration of phenytoin to mice leads to the induction of androgen receptor expression in the hippocampus [69].…”