Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00691 (EE2)
 7,802 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conscious unrestrained rats were stimulated through chronically-implanted electrodes in the median eminence-arcuate (ME-ARC), medial preoptic area (MPOA), amygdala (AMYG) or caudateputamen area of the brain on diestrus-2 of a 4-day estrous cycle or diestrus-3 of a 5-day cycle. Each rat was repeatedly tested after returning to normal cycles according to the following procedure: stimulation at current levels of 25, 50 or 100 muA (biphasic pulses), injection of 1 or 3 mug estradiol benzoate or 1 mg progesterone, and injection of the same hormones 24 h before stimulation at 50 muA. Indirect evidence of advanced ovulation, judged by the pattern of vaginal smears, was obtained depending on the current and site of stimulation: 25 muA was subthreshold for all brain areas, 50 muA was threshold for the ME-ARC and AMYG, and 75-100 muA was very effective in the ME-ARC, but could not be tested in the MPOA or AMYG due to abnormal behavior. Histological studies of the ovary revealed premature luteinization of some follicles and occasional advancement of ovulation. Pseudopregnancy-length diestrus often followed ovulation or advanced ovulation. This event was produced by a lower threshold current of 25 muA in the ME-ARC and MPOA. A current of 50 muA was maximally effective in the ME-ARC, but less so in the MPOA and AMYG; 75-100 muA caused successive periods of pseudoprengancy-length diestrus in the ME-ARC group. It is concluded that specificity of neural circuits from the AMYG to LHRH neurons is questionable since stimuli which led to reproductive changes also produced seizure activity. But stimuli producing no abnormal behavior in conscious rats clearly altered reproductive cycles when applied to the ME-ARC, and in the MPOA produced mino changes in cycles. Estradiol facilitated the effect of stimulation on early appearance of leucocytes in the vaginal smear in the estrous cycle and pseudopregnancy-length diestrus; contrarily, progesterone, in a few cases, inhibited both effects.
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PMID:Estrous cycles after electrical stimulation of the brain in conscious rats: effect of current strength, estradiol benzoate and progesterone. 55 3

Estradiol alters cognitive function and lowers the threshold for seizures in women and laboratory animals. Both of these activities are modulated by the excitatory neurotransmitter glutamate in the hippocampus. To assess the hypothesis that estradiol increases the sensitivity of the hippocampus to glutamate activation by increasing glutamate binding sites, the densities of N-methyl-D-aspartate (NMDA) agonist sites (determined by NMDA displaced glutamate), competitive antagonist sites (CGP 39653), noncompetitive antagonist sites (MK801) as well as the non-NMDA glutamate receptors for kainate and AMPA (using kainate and CNQX, respectively) were measured using autoradiographic procedures. Two days of estradiol treatment increased the density of NMDA agonist, but not of competitive nor noncompetitive NMDA antagonist binding sites exclusively in the CA1 region of the hippocampus. The density of noncompetitive NMDA antagonist sites, however, was decreased in the dentate gyrus by estradiol treatment. Ovarian steroids had no effect on the density of kainate or AMPA receptors in any region of the hippocampus examined. These data indicate that the agonist and antagonist binding sites on the NMDA receptor/ion channel complex are regulated independently by an as yet unidentified mechanism, and that this regulation exhibits regional specificity in the hippocampus. The increase in NMDA agonist sites with ovarian hormone treatment should result in an increase in the sensitivity of the hippocampus to glutamate activation which may mediate some of the effects of estradiol on learning and epileptic seizure activity.
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PMID:Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus. 135 42

Ovarian steroids modulate learning, memory, and epileptic seizure activity, functions that are mediated in part by the hippocampus. Normal function depends on precise interactions between the inhibitory gamma-aminobutyric acid (GABA)ergic and excitatory glutamatergic neurons of the hippocampus. To determine whether estradiol and progesterone interact with GABAergic neurons, the levels of mRNA for glutamic acid decarboxylase (GAD), the rate-limiting enzyme for GABA synthesis, were measured by in situ hybridization histochemistry with 35S-labeled riboprobes complimentary to the feline GAD cDNA. The levels of mRNA for GAD were analyzed in selected region of the dorsal hippocampus and medial basal hypothalamus in ovariectomized, ovariectomized estradiol-treated, and ovariectomized estradiol- and progesterone-treated rats. In estradiol-treated rats, GAD mRNA levels increased in GABAergic neurons associated with the CA1 pyramidal cell layer, but not in the stratum oriens of CA1 or any other region of the hippocampus. Estradiol plus progesterone treatment reversed the estradiol-induced increase in GAD mRNA in CA1 and induced a small decrease in the hilus. No effect of estradiol or progesterone was observed in the dorsomedial, ventromedial, or arcuate nuclei of the hypothalamus. Estradiol or progesterone may alter cognitive performance and seizure activity by increasing or decreasing, respectively, the activity of GABAergic neurons in the hippocampus.
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PMID:Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus. 144 11

Animal experimental and human clinical investigations show that estrogens lower and progestins raise many seizure thresholds. In women, seizure frequency varies with the serum estradiol to progesterone ratio. The fluctuation of this ratio during the menstrual cycle is a major factor in catamenial epilepsy. A decline in serum antiseizure medication levels premenstrually may be another factor. Estradiol to progesterone ratios are elevated in anovulatory or inadequate luteal phase cycles. This may explain a propensity for seizure onset at the time of menarche and the exacerbation of seizures during the months or years leading up to menopause. It may also be an important factor in the association between reproductive endocrine disorders and epilepsy. Specifically, polycystic ovarian syndrome and hypogonadotropic hypogonadism are significantly overrepresented among women with epilepsy. Epilepsy may promote the development of these disorders. These disorders, in turn, are characterized by inadequate luteal phase cycles that may promote the development or occurrence of seizures. In the setting of catamenial epilepsy or reproductive endocrine disorders, progestins, such as natural progesterone and parenteral medroxyprogesterone, or antiestrogenic agents, such as clomiphene, constitute rational and effective adjuncts to therapy.
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PMID:Reproductive endocrine considerations and hormonal therapy for women with epilepsy. 195 9

Androgen deficiency is unusually common among men with epilepsy. It may contribute to reproductive and sexual dysfunction and possibly exacerbate seizure frequency. The most important androgen is testosterone. it exists in the serum in a free form or bound to albumin or sex hormone-binding globulin (SHBG). Free testosterone levels have correlated significantly with measures of potency and sexual interest. The possibility that measures of non-SHBG-bound testosterone may provide a more sensitive assessment of biologically and perhaps clinically significant androgen levels is raised for consideration. Androgen deficiency may result from increased catabolism and binding induced by antiepileptic drugs (AEDs). It is a feature of the reproductive endocrine disorders that are often associated with epilepsy: hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, and functional hyperprolactinemia. It may be a consequence of medication-induced elevations in serum estradiol. Estradiol exerts a potent inhibitory influence on luteinizing hormone secretion and may contribute to premature aging of the reproductive system, both at the level of the testes and the hypothalamus. Testosterone therapy may moderately benefit reproductive and sexual function. Despite its antiseizure effects in animal experiments, however, it has not been reported to improve seizures clinically. One possible explanation is that AEDs that induce enzyme synthesis may enhance the conversion of testosterone to estradiol by aromatase. This possibility is supported by the improved seizure control achieved with the adjunctive use of the aromatase inhibitor testolactone or the antiestrogen clomiphene.
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PMID:Reproductive endocrine considerations and hormonal therapy for men with epilepsy. 195 10

Estradiol replacement facilitates amygdala and neocortical kindling. This study determined if estradiol also interacts with kindling of additional limbic sites, the dorsal (dH) and ventral (vH) hippocampus. During dH stimulations, ovariectomized female rats with estradiol (E) replacement required 29.7 +/- 3.5 trials to kindle and accumulated 1170 +/- 90 s of afterdischarge (AD), significantly less than the 40.6 +/- 3.7 trials and 1620 +/- 225 s in rats without estradiol (nE). E did not significantly alter the long series of partial limbic seizures preceding generalized seizures despite the early appearance of AD in the contralateral amygdala. E significantly advanced the onset of generalized seizures compared to nE (22.7 +/- 2.3 versus 27.9 +/- 3.2 trials), an event coincident with neocortical AD development. Following secondary seizure generalization, E rats rapidly completed late-kindled seizure acquisition. In contrast, nE rats required an almost twofold greater number of AD trials and AD s to complete late kindling compared to E rats. One factor in the slower late kindling of nE rats was the instability of generalized seizures which frequently regressed to focal or partial responses. In marked contrast to dH kindling, vH kindling was uneffected by E replacement. The results provide further experimental evidence for a role for estradiol in catamenial epilepsy and support our previous work suggesting that the focal origin of seizure development is critical to E facilitation of kindling and that secondary generalization of seizures is especially sensitive to estradiol.
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PMID:Estradiol replacement to female rats facilitates dorsal hippocampal but not ventral hippocampal kindled seizure acquisition. 198 33

Estradiol replacement facilitates kindling from a limbic region, the amygdala. This study determined if estradiol also interacts with kindling from a non-limbic region, the anterior neocortex. Ovariectomized female rats with estradiol replacement required 24 +/- 1.6 trials to kindle and accumulated 434 +/- 28 sec of afterdischarge (AD), significantly less than the 38 +/- 2.2 trials and 840 +/- sec in rats without estradiol. Estradiol replacement did not significantly alter the long series of focal cortical seizures preceding generalized seizures in spite of the early appearance of AD in the contralateral amygdala. Estradiol significantly advanced the onset of generalized seizures compared to rats without estradiol (19 +/- 0.6 versus 24 +/- 1.9 trials). Following secondary seizure generalization, estradiol rats rapidly completed late kindled seizure acquisition. In contrast, late kindling in rats without estradiol was slower as reflected by a 3-fold greater number of AD trials and AD seconds to complete kindling compared to rats with estradiol. One factor in the slower late kindling of rats without estradiol was the instability of generalized seizures which frequently regressed to focal or partial responses. The results provide further experimental evidence for a role for estradiol in catamenial epilepsy and suggest that the process of secondarily generalization of seizures is especially sensitive to estradiol.
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PMID:Estradiol replacement facilitates the acquisition of seizures kindled from the anterior neocortex in female rats. 261 93

A leading patient complaint is headaches which tend to occur more often in women than men. Nonvascular headache is the most common and is caused by tension or muscle contraction. Oral contraceptives (OCs) do not affect nonvascular headaches. They can also be safely used in women who experience common migraines whose symptoms do not become more severe or frequent during OC use. On the other hand, women who have classic migraine (headache accompanied by focal neurologic symptoms) or common migraine with symptoms becoming more severe or frequent during OC use should discontinue OC use. Instead, they should use a barrier method or the IUD. Estradiol treatment appears to be effective in treating menstrual migraine. Since the data are inconclusive about the effect of OCs on young women who have experienced a stroke or transient ischemic attacks, it would be best for them to use a barrier method. Most antiepileptic drugs (phenobarbital, phenytoin, paramethadione, and carbamazepine) cause enzyme induction which may be linked to decreased levels of estrogen and increases in irregular bleeding, thereby increasing the likelihood of an epileptic OC user becoming pregnant. Possible contraceptive failure exposes a developing fetus to the teratogenic properties of the antiepileptic drugs. Thus, physicians should prescribe OCs with 50 mcg of ethinyl estradiol rather than 35 mcg ethinyl estradiol. Epileptic women can also use Depo-Provera, because it is not only effective in preventing pregnancy but reduces seizure frequency. It is important for any contraceptive method chosen for epileptic women to be effective because pregnancy intensifies seizures which in turn can damage the mother and/or fetus and cause neonatal distress.
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PMID:Contraceptive methods for women with neurologic disorders. 851 48

Tramadol is a centrally acting, binary analgesic that is neither an opiate-derived nor a nonsteroidal anti-inflammatory drug and that was approved for use in the United States in 1995. It is used to control moderate pain in chronic pain settings such as osteoarthritis and postoperative cases. Used in therapy as a racemic mixture, the (+)-enantiomer weakly binds to the mu-opioid receptor, and both enantiomers inhibit serotonin and norepinephrine reuptake. Tramadol's major active metabolite, O-desmethyltramadol (ODT), shows higher affinity for the mu-opioid receptor and has twice the analgesic potency of the parent drug. The synergism of these effects contributes to tramadol's analgesic properties with the (+)-enantiomer exhibiting 10-fold higher analgesic activity than the (-)-enantiomer. Although tramadol was initially thought to exhibit low abuse potential, Ortho-McNeil, the drug's manufacturer, recently reported a large number of adverse events attributed to tramadol including abuse by opioid-dependent patients, allergic reactions, and seizures. The high number of adverse reactions has prompted the company to update the prescribing information for the drug. An analytical method using gas chromatography-mass spectrometry (GC-MS) without derivatization for the determination of tramadol and its metabolites is reported. An n-butyl chloride extraction is followed by GC-MS analysis using a 5% phenylmethylsilicone column (30 m x 0.32-micron i.d.). Analysis of 12 blood samples from tramadol-related deaths and four nonfatal intoxications involving tramadol revealed concentrations ranging from 0.03 to 22.59 mg/L for tramadol, from 0.02 to 1.84 mg/L for ODT, and from 0.01 to 2.08 mg/L for N-desmethyltramadol. Three deaths were clearly attributable to acute morphine toxicity, one was a doxepin overdose, and six were multiple drug overdoses. The role of tramadol in each death is explored.
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PMID:Identification of tramadol and its metabolites in blood from drug-related deaths and drug-impaired drivers. 939 21

The ovarian steroid hormone estradiol, in addition to its function in the maintenance and regulation of reproductive capacity, can alter neuronal excitability. Estradiol is proconvulsant, increases neuronal excitability and decreases the threshold for seizure activity. Over one-third to one-half of women with epilepsy experience catamenial seizures, which are seizures influenced by cyclical hormone changes. These hormone-sensitive seizures respond to the anti-epileptic drug gabapentin, which is a structural analogue of the inhibitory amino acid neurotransmitter GABA. We studied the effects of 17-beta-estradiol alone and estradiol co-incubated with gabapentin on neuronal activity in network cultures of rat hippocampal neurons using a fluorescent calcium binding dye fluo-3 AM, FM 1-43 labeling of synaptic vesicles and electrophysiological recordings. Significant changes in the neuronal network activity were observed in the estradiol-treated neuronal cultures; the reactivity of the neurons to KCl depolarization induced intracellular calcium changes, and FM 1-43 destaining was increased as was the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSC). All these excitatory effects of estradiol were nullified by co-incubating the neurons with a combination of estradiol and gabapentin. This suggests that gabapentin can indeed affect the estradiol-induced changes in neuronal network hyperexcitability by influencing the neuronal calcium levels, exocytosis and synaptic activity. Our findings could provide an understanding of the cellular basis of hormone-sensitive seizure control by gabapentin.
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PMID:Estradiol-induced changes in the activity of hippocampal neurons in network culture are suppressed by co-incubation with gabapentin. 1535 22


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