Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in gonadal steroid hormone levels during the menstrual cycle affect seizure frequency in women with catamenial epilepsy. Since GABA(A) receptors (GABARs) contribute to the prevention and termination of seizures by reducing neuronal excitability, we hypothesized that fluctuating gonadal steroid levels might affect GABAR subunit expression, which could alter inhibitory tone leading to increased seizure activity. To address this question in a simplified environment in vitro, we examined the effects of gonadal steroids on NT2-N neuronal cells. We have previously shown that NT2-N cells express functional GABARs, and that the expression pattern of GABAR subunits is regulated by chronic benzodiazepine exposure and hypoxia. NT2-N neurons were exposed to progesterone (0.1 microM), beta-estradiol (3 nM), or vehicle (DMSO) for 2 days or 7 days prior to RNA harvesting. GABAR subunit mRNA levels were assessed by semiquantitative RT-PCR normalized to actin levels. Progesterone exposure for 7 days increased alpha2 and gamma3 and decreased alpha5 subunit mRNAs, while beta-estradiol caused significant increases in alpha3, beta3 and epsilon expression. Further analysis revealed differential regulation of alpha4, alpha5, epsilon and pi subunit expression. Plots of relative PCR density in progesterone-treated cells for alpha2 vs. alpha5, alpha5 vs. gamma3 and alpha2 vs. gamma3 showed correlation between samples, suggesting coordinate regulation. Both progesterone and estrogen nuclear receptor mRNAs were detected by RT-PCR, and 2 days but not 7 days estrogen exposure upregulated progesterone receptor mRNA. Gonadal steroid fluctuations regulate GABA(A) receptor subunit expression in NT2-N cells. Such changes, if observed in vivo, could affect seizure frequency.
 ...
PMID:Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-N neurons. 1600 Feb 29

Estrogen can be proconvulsant, while progesterone and its metabolite allopregnanolone typically have anti-seizure effects. We investigated whether estrogen-priming also has anti-seizure effects by altering progesterone's metabolism to allopregnanolone, or levels of brain-derived neurotrophic factor (BDNF), in the hippocampus. Two experiments investigated effects of different estrogen-priming regimen (Experiment 1--10 microg; Experiment 2--2 microg) on pentylenetetrazole (PTZ)-induced seizures and levels of estrogen, progesterone and allopregnanolone in plasma and hippocampus. In Experiment 1, ovariectomized (ovx) rats were administered sesame oil vehicle or 10 microg 17beta-estrogen at hour 0. Forty-four hours later, progesterone (500 microg; s.c.) or vehicle was administered. At hour 47, PTZ (70 mg/kg i.p.) was administered. For Experiment 2, a similar protocol was used except that ovx rats were administered vehicle or 2 microg 17beta-estradiol at hours 0 and 24. Progesterone, alone or in conjunction with either 10 or 2 microg estrogen-priming, tended to increase the latency to, and significantly reduced the number of, tonic seizures and elevated levels of progestins in hippocampus and plasma. Two, but not 10, micrograms of estrogen alone had anti-seizure effects and increased levels of allopregnanolone in the hippocampus. BDNF levels in the hippocampus were increased by estrogen-priming, but reduced by progesterone administration. Thus, estrogen may have anti-seizure effects by enhancing formation of allopregnanolone.
 ...
PMID:Estrogen-priming can enhance progesterone's anti-seizure effects in part by increasing hippocampal levels of allopregnanolone. 1608 96

Both steroid hormones and neurosteroids affect seizure expression and propagation in the central nervous system (CNS). Progesterone and allodeoxycorticosterone exhibit anticonvulsant, while estradiol and cortisol present proconvulsant action. Effect of testosterone on seizure phenomena depends on the metabolic route that this androgen is involved in. Natural (allopregnanolone) or synthetic (alphaxolone, ganaxolone, Co 21068) neuroactive steroids show protective effect against variety of experimental seizures, including electrically-triggered convulsions, like maximal electroshock, electrical kindling, and chemically-evoked, like pilocarpine-, pentetrazole-, picrotoxin-, cocaine-, bicuculline-, kainate-, or NMDA-induced ones. Influence of neurosteroids on seizure processes results from their ability to modulate two basic neurotransmitter systems, glutamatergic (mainly through NMDA receptors) and GABA-ergic (realized by GABAA receptors). Neuroactive steroids devoid of hormonal activity, but they preserve the action on neuronal excitability. The anticonvulsant efficacy of allopregnanolone, one of the natural neurosteroids, is greater than that of its hormonal precursor. However, a therapeutic application of natural neuroactive steroids is significantly limited by their rapid biotransformation. Synthetic derivatives are orally-active and their half-life time is essentially longer. Therefore, neurosteroids are good drug candidates for both monotherapy and add-on treatment of epilepsy. The best examined neurosteroid, ganaksolone, is currently under phase II clinical investigation.
 ...
PMID:[Perspectives of neurosteroid derivative application in antiepileptic therapy]. 1651 23

Progesterone is a neurosteroid that modulates neuronal excitability. The anticonvulsant effects of progesterone are largely mediated by the actions of its metabolites. The purpose of this study was to measure the anticonvulsant effects of progesterone, 5alpha-dihydroprogesterone, and allopregnanolone against amygdala-kindled seizures in male rats. The amygdala kindling model is a model of human complex partial seizures with secondary generalization. A bipolar electrode was chronically implanted in the right amygdala of male Wistar rats. All subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone, 5alpha-dihydroprogesterone, or allopregnanolone were administered in separate dose-response studies. The antiseizure effects of each compound were determined. A progesterone time-response study was also conducted. At 30 min after injection, progesterone had an ED50 of 65.3 mg/kg against the secondarily generalized seizure and an ED50 of 114 mg/kg against the focal seizure. 5alpha-dihydroprogesterone had a low ED50 of 6.2 mg/kg against both the generalized component of the amygdala-kindled seizure and the focal seizure. Allopregnanolone had an ED50 of 15.2 mg/kg against the secondarily generalized seizure and was not effective against the focal seizure. Progesterone is an effective anticonvulsant against the secondarily generalized component of amygdala-kindled seizures in male rats. Progesterone is only effective against the focal seizure at high ataxic doses. 5alpha-dihydroprogesterone is a potent anticonvulsant against both the kindled amygdala focal discharge and the secondarily generalized seizure. Allopregnanolone is an effective anticonvulsant against the secondarily generalized component of the seizure, but not against the amygdala focal discharge.
 ...
PMID:The anticonvulsant effects of progesterone and its metabolites on amygdala-kindled seizures in male rats. 1678 31

Classical theories on absence epilepsy suggest that spike-wave discharge (SWDs) represent thalamo-cortical oscillations, where an abnormally excitable cortex interacts with thalamus and brain stem reticular formation. The limbic system is generally not included in any theory about the pathogenesis of absence seizures. However, some data demonstrated that the alterations in the limbic system attribute to the expression of absence epileptic phenotype in genetic models of absence epilepsy. The present study investigated whether local intrahippocampal administration of progesterone (a GABA(A)-mimetic) and tiagabine (an inhibitor of GABA (re)uptake) might affect the occurrence of SWDs. Male WAG/Rij rats were implanted with permanent electroencephalograph (EEG) electrodes and bilateral cannulas in the CA1-CA3 region of the dorsal hippocampus. Control rats had bilateral cannulas in the cortical area above the hippocampus. Rats received intracerebral injections of progesterone (5mg/ml), 45% beta-cyclodextrin (CD), saline, or tiagabine (2mg/ml). EEG recordings were made before and after injection. Progesterone, CD, and tiagabine administration to the hippocampus reduced SWDs for 60min following administration without behavioral or electroencephalographic side-effects. Both progesterone administration into the cortex and saline injection into the hippocampus yielded no changes in the occurrence of SWDs. These data suggest that activation of GABA-ergic transmission in the hippocampus has an inhibitory effect on cortico-thalamo-cortical circuits underlying the generation of SWDs and might be critically involved in the regulation of absence seizures.
 ...
PMID:Absence seizures are reduced by the enhancement of GABA-ergic inhibition in the hippocampus in WAG/Rij rats. 1728 Jul 80

Clinical decision making which contraceptive regimen is optimal for an individual woman with epilepsy is one of the most challenging tasks when taking care of women with epilepsy. The bidirectional interactive potential of antiepileptic drugs (AEDs) and hormonal contraceptives needs to be taken into account. Enzyme inducing (EI)-AEDs may reduce the contraceptive efficacy of hormonal contraceptives. If combined oral contraceptives (COCs) are used in combination with EI-AEDs, it is recommended to choose a COC containing a high progestin dose, well above the dose needed to inhibit ovulation, and to take the COC pill continuously ("long cycle therapy"). But even with the continuous intake of a COC containing a higher progestin dose contraceptive safety cannot be guaranteed, thus additional contraceptive protection may be recommended. Progestin-only pills (POPs) are likely to be ineffective, if used in combination with EI-AEDs. Subdermal progestogen implants are not recommended in patients on EI-AEDs, because of published high failure rates. Depot medroxyprogesterone-acetate (MPA) injections appear to be effective, however they may not be first choice due to serious side effects (delayed return to fertility, impaired bone health). The use of intrauterine devices is an alternative method of contraception in the majority of women, with the advantage of no relevant drug-drug interactions. The levonorgestrel intrauterine system (IUS) appears to be effective, even in women taking EI-AEDs. Likelihood of serious side effects is low in the IUS users.
Seizure 2008 Mar
PMID:Which contraception for women with epilepsy? 1817 10

The possible neuroprotective effect of progesterone, a steroid hormone, on acute phase changes in a mouse model of cerebral ischaemia induced by bilateral common carotid artery occlusion (BCAO) was studied. A total of 72 male mice were included in the study. The BCAO model was used to induce partial global cerebral ischaemia. Morphological assessment included measurement of infarct size and brain oedema. Post-ischaemic seizure susceptibility was assessed using a subconvulsive dose of pentylenetetrazole (30 mgkg(-1) i.p.). Biochemical estimations included tumour necrosis factor alpha (TNF-alpha) levels and enzyme parameters such as lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase, and protein estimation. BCAO induced a significant infarct size and oedema in the saline-treated control group, along with an increase in oxidative stress, indicated by increased lipid peroxidation and decreased levels of antioxidants such as superoxide dismutase, catalase and glutathione peroxidase. Progesterone (15 mgkg(-1) i.p.) administration showed a neuro-protective effect by significantly reducing the cerebral infarct size as compared with the control group. Post-ischaemic seizure susceptibility was also reduced as the number of positive responders decreased. Brain oedema subsided, but not significantly. Progesterone significantly reduced TNF-alpha levels compared with the ischaemia group. Progesterone improved levels of all the antioxidants, indicating activity against oxidative stress induced by BCAO. The results demonstrate the neuroprotective effect of progesterone against ischaemic insult, suggesting a role for the steroid as a neuroprotective agent.
 ...
PMID:Neuroprotective effect of progesterone on acute phase changes induced by partial global cerebral ischaemia in mice. 1849 9

Described here is an investigation of the potential interaction of the nitric oxide signaling pathway with the anticonvulsant effects of progesterone. In ovariectomized Swiss mice, the threshold for seizures induced by intravenous infusion of pentylenetetrazole was determined after treatment with progesterone (25, 50, or 75 mg/kg, given subcutaneously 6h before seizure testing) or vehicle. Progesterone induced significant anticonvulsive activity at moderate (50 mg/kg) and high (75 mg/kg) doses. This effect of progesterone was abolished by the NO precursor compound L-arginine (200 mg/kg). Moreover, when subeffective doses of progesterone (25 mg/kg) and the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (10 mg/kg) were injected, a strong anticonvulsant effect was observed. These findings suggest a potential role for NO signaling as an anticonvulsant target in females.
 ...
PMID:Role of nitric oxide in the anticonvulsive effect of progesterone. 1870 62

Catamenial epilepsy is defined by the cyclical seizure exacerbation seen in almost 40% of women with epilepsy. The pattern appears to be related to predominance of estrogen over progesterone during the pre-ovulatory and/or perimenstrual days of the ovulatory menstrual cycle or during the broad period between day 14 and menstruation in anovulatory cycles with inadequate luteal progesterone levels. Progesterone affects central nervous excitability in an "inhibitory" manner, slowing kindling and decreasing seizure susceptibility in animal models. Estrogen enhances kindling and decreases after discharge threshold. These neurosteroidal hormones alter the GABA-A receptor in cell cultures and in animal models. Treatment of this clinical syndrome has been empirical and reported in a small series of women. Progesterone therapy and possible new approaches with synthesized neurosteroids may offer a promising approach to improve seizure control in women with catamenial epilepsy.
 ...
PMID:Catamenial epilepsy. 1892 76

Single seizure and epilepsy is one of the most commonly encountered neurologic disorders in elderly individuals, arising as a result of complex and often multiple acquired underlying pathologies. Adenosine, acting at A1 receptors, exhibits anticonvulsant effects in experimental epilepsy and inhibits progression to status epilepticus. Adenosine deaminase is the enzyme for the regulation of adenosine levels. Therefore any change in adenosine deaminase levels will reflect to adenosine levels. Adenosine deaminase levels were decreased in the groups that were given progesterone. Progesterone may have an antiseizure effect with the additional finding decreased levels of adenosine deaminase that would have resulted in increased adenosine levels that exerts anticonvulsant effect via GABA-A receptors. Further studies are needed to evaluate the role of progesterone effects on adenosine deaminase levels and its mechanism(s) in the pathogenesis.
 ...
PMID:Effects of progesterone on total brain tissue adenosine deaminase activity in experimental epilepsy. 1912 74


<< Previous 1 2 3 4 5 6 Next >>