Phenytoin Is an Estrogen Receptor α-Selective Modulator That Interacts With Helix 12

Fadiel, Ahmed; Song, J. J.; Tivon, Doreen; Hamza, Adel; Cardozo, Timothy; Naftolin, Frederick

doi:10.1177/1933719114549853

Cited by 14 publications

(9 citation statements)

References 52 publications

(69 reference statements)

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“…The activation of ER was suggested to be responsible for the anticonvulsant effects of oestrogen (Frye, Ryan, & Rhodes, 2009). On the other hand, the commonly prescribed antiepileptic drug phenytoin, behaving as a powerful antagonist of oestradiol but producing agonistic actions in the absence of oestradiol, was characterized as an ER -selective ER modulator (SERM) (Fadiel et al, 2015), which explains the varying efficiency of the drug correlated with the changes in ovarian functions (Hines & Murphy, 2011;Juurlink, Mamdani, Kopp, Laupacis, & Redelmeier, 2003). The GPER-1 receptor was shown to mediate the epileptogenic effect of oestrogen by modulating the oxidative or antioxidative status of the brain tissue (Kurt, Bosnak, Inan, Celik, & Uremis, 2016), while pretreatment with a phyto-oestrogen has exhibited anticonvulsant and neuroprotective effects by improving oxidative stress and apoptosis (Amiri et al, 2017;Elsayed et al, 2018).…”

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confidence: 99%

Oestrogen receptor ERα and ERβ agonists ameliorate oxidative brain injury and improve memory dysfunction in rats with an epileptic seizure

Koyuncuoğlu

Tamer

Erzik

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Could different hormonally active substances, including oestrogen receptor (ER) agonists, protect against oxidative brain damage and memory impairment induced by a single epileptic seizure in rats? If so, which signalling mechanisms are involved in their anti‐inflammatory effects? What is the main finding and its importance?Chronic administration of oestrogen, progesterone, ER modulators/agonists or blockade of testosterone exhibited anti‐inflammatory and antioxidant actions on single seizure‐induced neuronal injury, while ER agonists additionally improved memory function and up‐regulated CREB signalling and hippocampal GABA(A)α1 receptor density, suggesting that ERα or ERβ receptor activation may be beneficial in protecting against seizure‐related oxidative brain injury and cognitive dysfunction. Abstract The susceptibility to epileptic seizures is dependent on sex as well as fluctuations in oestrogen levels, while exogenous oestrogen was shown to have no effect or to facilitate or to inhibit seizure activity. Oestrogen receptors (ERs) mediate antioxidant and anti‐inflammatory actions in several inflammatory models, but the involvement of ERs in seizure‐induced neuronal injury has not been evaluated previously. In order to assess the effects of resveratrol, progesterone, oestradiol (E2), an anti‐testosterone (cyproterone acetate; CPA), a selective ER modulator (tamoxifen; TMX) and ERα/ERβ agonists (propyl pyrazole triol (PPT), diarylpropionitrile (DPN)) on oxidative brain damage and memory impairment due to epileptic seizure, male Wistar rats (n = 120) received one of the treatment choices either in drinking water or intraperitoneally for 31 days, and epileptic seizure was induced on the 28th day by injection of a single‐dose of pentylenetetrazole (45 mg kg−1). The results demonstrate that chronic pretreatment with resveratrol, progesterone, E2, CPA or TMX suppressed most of the inflammatory parameters indicative of oxidative neuronal injury, while treatment with the ER agonists DPN or PPT were found to be even more effective in limiting the oxidative damage. Treatment with DPN resulted in the up‐regulation of cAMP response element‐binding protein (CREB) and brain‐derived neurotrophic factor (BDNF) expression, while PPT up‐regulated expression of CREB without affecting BDNF levels. Moreover, both ER agonists provided protection against seizure‐induced memory loss with a concomitant increase in hippocampal GABA(A)α1‐positive cells. In conclusion, ER agonists, and more specifically ERβ agonist, appear to provide maximum protection against seizure‐induced oxidative brain injury and associated memory dysfunction by up‐regulating the expression of CREB, BDNF and GABA(A)α1 receptors.

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confidence: 99%

Oestrogen receptor ERα and ERβ agonists ameliorate oxidative brain injury and improve memory dysfunction in rats with an epileptic seizure

Koyuncuoğlu

Tamer

Erzik

et al. 2019

Experimental Physiology

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“…Fadiel et al 63 found that PHEN is a strong estrogen receptor α antagonist at clinically achievable concentrations and at the same time is a weak agonist.…”

Section: Resultsmentioning

confidence: 99%

Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs

Koltai¹

2015

F1000Res

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Objective: To determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage gated sodium channel blocking properties. Material and methods: A review of the published medical literature was performed searching for pharmaceuticals used in daily practice, with inhibitory activity on voltage gated sodium channels. For every drug found, the literature was reviewed in order to define if it may act against cancer cells as an anti-invasion and anti-metastatic agent and if it was tested with this purpose in the experimental and clinical settings. Results: The following pharmaceuticals that fulfill the above mentioned effects, were found: phenytoin, carbamazepine, valproate, lamotrigine, ranolazine, resveratrol, ropivacaine, lidocaine, mexiletine, flunarizine, and riluzole. Each of them are independently described and analyzed. Conclusions: The above mentioned pharmaceuticals have shown anti-metastatic and anti-invasion activity and many of them deserve to be tested in well-planned clinical trials as adjunct therapies for solid tumors and as anti-metastatic agents. Antiepileptic drugs like phenytoin, carbamazepine and valproate and the vasodilator flunarizine emerged as particularly useful for anti-metastatic purposes.

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“…The instructors introduced the class to recent studies reporting on drugs such as dobutamine and phenytoin that are used to treat heart failure and epilepsy respectively, which may interfere with a patient's response to drugs such as tamoxifen. 10,11 Similar events may also occur when patients are coadministered tamoxifen and nutritional supplements containing phytoestrogens such as liquiritigenin. 12 The instructors explained that this type of competition of drugs for binding to the estrogen receptor may lead to drug-drug interactions.…”

Section: Methodsmentioning

confidence: 99%

Development of a Course-Based Undergraduate Research Experience to Introduce Drug-Receptor Concepts

Swanson

Sarge

Rodrigo-Peiris

et al. 2016

Journal of Medical Education and Curricular Development

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Course-based research experiences (CUREs) are currently of high interest due to their potential for engaging undergraduate students in authentic research and maintaining their interest in science, technology, engineering, and mathematics (STEM) majors. As part of a campus-wide initiative called STEMCats, which is a living learning program offered to freshman STEM majors at the University of Kentucky funded by a grant from Howard Hughes Medical Institute, we have developed a CURE for freshmen interested in pursuing health care careers. Our course, entitled “Drug–Drug Interactions in Breast Cancer,” utilized a semester-long, in-class authentic research project and instructor-led discussions to engage students in a full spectrum of research activities, ranging from developing hypotheses and experimental design to generating original data, collaboratively interpreting results and presenting a poster at a campus-wide symposium. Student's feedback indicated a positive impact on scientific understanding and skills, enhanced teamwork and communication skills, as well as high student engagement, motivation, and STEM belonging. STEM belonging is defined as the extent to which a student may view the STEM fields as places where they belong. The results obtained from this pilot study, while preliminary, will be useful for guiding design revisions and generating appropriate objective evaluations of future pharmacological-based CUREs.

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Phenytoin Is an Estrogen Receptor α-Selective Modulator That Interacts With Helix 12

Cited by 14 publications

References 52 publications

Oestrogen receptor ERα and ERβ agonists ameliorate oxidative brain injury and improve memory dysfunction in rats with an epileptic seizure

Oestrogen receptor ERα and ERβ agonists ameliorate oxidative brain injury and improve memory dysfunction in rats with an epileptic seizure

Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs

Development of a Course-Based Undergraduate Research Experience to Introduce Drug-Receptor Concepts

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