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

To examine the role of progesterone (P) and its 5alpha-reduced metabolite, the neurosteroid 5alpha-pregnan-3alpha-ol-20-one (3alpha, 5alpha-THP), in endogenous variations in ictal activity rats were tested for kainic acid-induced seizures in different hormonal milieu. Corresponding plasma and central P and 3alpha,5alpha-THP levels were measured. Cycling Long-Evans rats in estrus and proestrus had seizures of significantly shorter duration and more central and plasma 3alpha,5alpha-THP and P than animals in metestrus or diestrus. Females with luteal functioning had seizures of significantly shorter duration and increased central and plasma 3alpha,5alpha-THP and P compared to animals that recently had luteal functioning discontinued. Pregnant rats had significantly shorter seizures and greater central and plasma 3alpha,5alpha-THP and central P than animals tested 1-2 days postparturition. In all test paradigms, seizure activity was increased in animals that had decreased 3alpha, 5alpha-THP or P; overall, central 3alpha,5alpha-THP was more inversely related to ictal activity than central P or plasma P and 3alpha,5alpha-THP. To investigate a causal relationship between 3alpha,5alpha-THP and seizures, a 5alpha-reductase inhibitor, finasteride, or vehicle was administered to pregnant rats. Finasteride administration significantly decreased central and plasma 3alpha,5alpha-THP, but had no significant effect on plasma or central P of pregnant rats. Finasteride, but not vehicle administration, to pregnant rats significantly increased seizure duration. These findings support the hypothesis that variations in seizure threshold over endogenous hormonal milieu may be related to endogenous 3alpha,5alpha-THP. Of all of the endocrine conditions, seizure durations were greatest in diestrus animals; this group did not experience the lowest or the greatest decrease in 3alpha, 5alpha-THP concentrations; however, of all of the endocrine conditions, cycling rats experienced the most rapid cycles of 3alpha, 5alpha-THP variation. This suggests that cycles of endogenous variations in 3alpha,5alpha-THP may influence seizure threshold.
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PMID:Seizure activity is increased in endocrine states characterized by decline in endogenous levels of the neurosteroid 3 alpha,5 alpha-THP. 977 42

Antiseizure effects of progesterone (P) and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha, 5alpha-THP) were investigated following continuous vs. discontinuous P exposure. In Experiments 1, 32 cycling Long-Evans rats were administered kainic acid (32 mg/kg SC), ictal behavior was examined, and plasma 3alpha,5alpha-THP levels were measured by radioimmunoassay. Proestrus/estrus rats showed less ictal activity and had elevated 3alpha,5alpha-THP levels prior to kainic acid compared to diestrus/metestrus subjects. In Experiment 2, 49 ovariectomized (ovx) rats were SC injected with estradiol benzoate (EB; 10 microg) and P (500 microg), to mimic estrus, or sesame oil vehicle (0.2 cc); all subjects were administered kainic acid. Rats tested with EB+P showed a reduced mean duration of full seizures and increased 3alpha,5alpha-THP, whereas those tested 24 h following EB+P had more tonic clonic seizures and lower 3alpha,5alpha-THP concentrations, comparable to ovx control animals. In Experiment 3, 49 ovx rats were stereotaxically implanted with bipolar electrodes into the perforant pathway. Prior to perforant pathway stimulation, rats received cholesterol or EB+P capsules for 1 month, continuously or intermittently. Irrespective of continuous or intermittent EB+P, the presence of progestins at the time of perforant pathway stimulation reduced partial seizure activity. Continuous EB+P capsules resulted in increased 3alpha,5alpha-THP levels compared to all other conditions, and less damage in the hilus of the hippocampus, compared to intermittent EB+P. These data confirm that P and 3alpha,5alpha-THP have antiseizure effects, and further suggest that repeated cycles of endogenous or exogenous P and/or 3alpha,5alpha-THP withdrawal influences seizure threshold and/or hippocampal integrity.
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PMID:Cyclic withdrawal from endogenous and exogenous progesterone increases kainic acid and perforant pathway induced seizures. 997 99

The effects of prenatal stress on the ability of the 5 alpha-reduced progesterone metabolite and neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP) to prevent seizures was examined. On gestational Day 18, pregnant rats were exposed to 20 min of restraint stress (prenatal stress condition) or no such stress (control condition). The adult, gonadectomized offspring exposed to the prenatal stress or control condition were administered 0.0, 4.0, or 8.0 mg/kg 3 alpha,5 alpha-THP 1 hr prior to testing for kainic-acid-induced (32 mg/kg SC) ictal activity. The rats exposed to prenatal stress tended to have more partial seizures and significantly more tonic clonic seizures that were of longer duration than the no prenatal stress rats. Four mg/kg 3 alpha,5 alpha-THP was sufficient to significantly reduce seizure duration of no prenatal stress females, compared to the 0.0 mg/kg dosage of 3 alpha,5 alpha-THP. Seizure duration was reduced in no prenatal stress females by a dose of 4 mg/kg 3 alpha,5 alpha-THP, whereas a dose of 8 mg/kg was required to obtain comparable seizure reduction in prenatally stressed females and males in both groups. There was attrition following kainic-acid testing; of the 18 animals in each group originally, 9 prenatally stressed males, 6 prenatally stressed females, 6 nonprenatally stressed males and 5 nonprenatally stressed females were able to be tested in the water maze and perfused. One week after seizures, there were no differences in the water maze performance of the remaining animals. There were fewer cresyl violet-stained neurons in the CA3 region of the hippocampus of prenatally stressed rats compared to the nonprenatally stressed rats. Basal plasma corticosterone was greater in prenatally stressed animals, but this was due to increases in females rather than males. Plasma 3 alpha,5 alpha-THP was not significantly different in prenatally stressed males and females compared to their no prenatal stress counterparts. These data suggest that the sensitivity to, or responsiveness of, 3 alpha,5 alpha-THP to prevent seizures is decreased after prenatal stress, particularly in females.
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PMID:Prenatal stress reduces the effectiveness of the neurosteroid 3 alpha,5 alpha-THP to block kainic-acid-induced seizures. 1020 98

Neuroactive steroids are synthesized de novo in brain, yet their physiological significance remains elusive. We provide biochemical, electrophysiological, and behavioral evidence that several specific actions of alcohol (ethanol) are mediated by the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP; allopregnanolone). Systemic alcohol administration elevates 3alpha, 5alpha-THP levels in the cerebral cortex to pharmacologically relevant concentrations. The elevation of 3alpha,5alpha-THP is dose- and time-dependent. Furthermore, there is a significant correlation between 3alpha,5alpha-THP levels in cerebral cortex and the hypnotic effect of ethanol. Blockade of de novo biosynthesis of 5alpha-reduced steroids using the 5alpha-reductase inhibitor finasteride prevents several effects of ethanol. Pretreatment with finasteride causes no changes in baseline bicuculline-induced seizure threshold but reverses the anticonvulsant effect of ethanol. Finasteride pretreatment also reverses ethanol inhibition of spontaneous neural activity in medial septal/diagonal band of Broca neurons while having no direct effect on spontaneous firing rates. Thus, elevation of 3alpha,5alpha-THP levels by acute ethanol administration represents a novel mechanism of ethanol action as well as an important modulatory role for neurosteroids in the CNS.
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PMID:Neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol. 1068 99

The mechanism by which progesterone has its anti-seizure effects is unknown. Progesterone has a high affinity for intracellular progestin receptors, but has weak actions at gamma-aminobutyric acid (GABA)(A) receptors complexes. The progesterone metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) is devoid of activity at intracellular progestin receptors but is a highly effective modulator of GABA(A) receptor complexes. Whether progesterones anti-seizure actions are due to effects of progesterone itself or its metabolite 3alpha,5alpha-THP was investigated. In experiment 1, 25 ovariectomized Long-Evans rats were subcutaneously (s.c.) injected with 0.0, 4.0 or 8.0 mg/kg progesterone or 3alpha,5alpha-THP, 10 min prior to systemic administration of 32 mg/kg kainic acid. Four and 8.0 mg/kg progesterone significantly reduced the duration of partial and full seizures, without influencing the latency to partial or full seizures, or the number of partial or full seizures. 3alpha, 5alpha-THP (4.0 mg/kg) significantly increased the latency to initial partial seizure, and decreased the number and duration of partial seizures. In experiment 2, 60 ovariectomized Long-Evans rats were stereotaxically implanted with bipolar electrodes into the perforant pathway. Prior to perforant pathway stimulation, rats were s.c. injected with either progesterone (4.0 mg/kg, n = 12), 3alpha, 5alpha-THP (4.0 mg/kg, n = 13), progesterone (4.0 mg/kg)+4MA (10.0 mg of a 5alpha-reductase inhibitor, 17b-N, N-diethylcarbamoyl-4-methyl-4-aza,5alpha-androstan-3-one, n = 12), 4MA+vehicle (n = 10), or sesame oil vehicle (n = 13). Administration of progesterone or 3alpha, 5alpha-THP, but not vehicle control, P+4MA, or 4MA, resulted in significant decreases in partial seizures. In experiment 3, whole brain progesterone and 3alpha,5alpha-THP were measured by radioimmunoassay in additional rats (n = 66) administered the hormonal milieu indicated in experiments 1 and 2. Data suggest anti-seizure effects of progesterone may be due, in part, to metabolism to 3alpha,5alpha-THP and subsequent actions at GABA(A) receptor complexes.
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PMID:Anti-seizure effects of progesterone and 3alpha,5alpha-THP in kainic acid and perforant pathway models of epilepsy. 1072 16

Whether progesterone (P(4)) and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) have anti-seizure effects through actions in the pontine reticular formation (PRF) was investigated. Concentrations of P(4) and 3alpha, 5alpha-THP in the PRF were greater in proestrous and hormone-primed rats, that are typically more resistant to seizure-induction, than diestrous and males rats. Ovx, Long-Evans rats with unilateral microinjections into the PRF of 3alpha,5alpha-THP (5 microg/0.2 microl), but not P(4) (11 microg/0.2 microl) or vehicle (beta-cyclodextrin), had a greater latency and lower incidence of tonic-clonic seizures induced by pentylenetetrazol (PTZ; 70 mg/kg, IP) administration. Infusions that missed the PRF were not effective. These data suggest 3alpha,5alpha-THP has anti-seizure effects in part through actions in the PRF.
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PMID:Infusion of 3alpha,5alpha-THP to the pontine reticular formation attenuates PTZ-induced seizures. 1103 99

Angiogenesis plays an important role in neovascularization in tumors. Glycodelin, a hormone-responsive protein, has been detected in tumors of reproductive organs and is found in high levels in the plasma of subjects with gynecological malignancies. Glycodelin is also found in the endothelial cells of the umbilical cord and in the blood vessels of tumors. In this study, we tested whether glycodelin-rich amniotic fluid and a synthetic peptide derived from the sequence of glycodelin peptide (Gp) might promote angiogenic response by examining the migration and tube formation in human umbilical cord vein endothelial cells (HUVECs). Increased migration and tube formation of HUVECs were found in the presence of amniotic fluid and Gp, and this increase was blocked by antibody to Gp and by an anti-vascular endothelial growth factor (VEGF) antibody, suggesting that the angiogenic effects of glycodelin might be mediated by VEGF. The results also showed that Gp significantly increased the release of VEGF protein and mRNA expression in HUVECs, RL-95 (human endometrial carcinoma cells), OVCAR-3 (human ovarian adenocarcinoma cells), EM42 (human endometrial epithelial cells), THP-1 (human monocyte), and MCF-7 and MDA-MB-231 (human breast adenocarcinoma cells) cell lines. VEGF receptor Fit-1 mRNA expression in HUVECs was also increased in the presence of Gp. These findings, together with the suggestion from the literature that glycodelin may have immunosuppressive properties, suggest that glycodelin might play an important role in neovascularization during embryogenesis and tumor development.
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PMID:Angiogenic role for glycodelin in tumorigenesis. 1145 32

Whether progesterone (P(4)) and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) have anti-seizure effects through actions in the raphe magnus (NRM) was investigated. Ovariectomized, Long-Evans rats with unilateral implants into the NRM of P(4) or its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) had a significantly lower incidence of myoclonic seizures and less EEG activity following pentylenetetrazol (PTZ; 70 mg/kg, IP) administration than did rats with control implants. Progestin implants that missed the NRM were not effective at reducing ictal activity. Following P(4) implants to the NRM levels of P(4), and following P(4) and 3alpha,5alpha-THP implants to the NRM, 3alpha,5alpha-THP levels in the ventral hindbrain were increased above those seen in rats with control implants. These data suggest that progestins' anti-seizure effects in the NRM may be involve actions of 3alpha,5alpha-THP.
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PMID:3alpha,5alpha-THP in the raphe magnus attenuates PTZ-induced myoclonic seizures. 1151 82

Early work in the field established that the 5 alpha-reduced metabolite of progesterone 3 alpha-OH-5 alpha-pregnan-20-one (allopregnanolone or 3 alpha,5 alpha-THP) is a potent positive modulator of the GABA(A) receptor (GABAR), the receptor mediating the effects of the primary inhibitory transmitter in the brain. This steroid acts in a manner similar to sedative drugs, such as the barbiturates, both in terms of potentiating GABA-induced inhibition in vitro and in behavioral assays, by reducing anxiety and seizure susceptibility. Because sedative compounds exhibit withdrawal properties that result in behavioral hyperexcitability, our laboratory has more recently investigated the effect of prolonged application and rapid removal (i.e. 'withdrawal') of this steroid, administered in vivo to female rats. Withdrawal from 3 alpha,5 alpha-THP produces a state of increased anxiety and lowered seizure threshold, similar to withdrawal from other GABA-modulatory drugs such as the benzodiazepines and alcohol. Hormone withdrawal also produced increases in the alpha 4-containing GABAR, an effect correlated with insensitivity of the GABAR to modulation by the benzodiazepine class of tranquilizers, as would normally occur under control conditions. In addition, changes in intrinsic channel properties, including a marked acceleration in the decay rate was also observed as a result of declining levels of 3 alpha,5 alpha-THP. Such a change would result in less inhibitory total current, and the resulting increase in neuronal excitability could then underlie the observed behavioral excitability following hormone withdrawal. These results suggest that actions of this steroid on a traditional transmitter receptor in the brain lead to alterations in GABAR subunit composition that result in changes in the intrinsic channel properties of the receptor and behavioral excitability. These results may have implications for endogenous fluctuations in this hormone which may accompany premenstrual dysphoric disorder.
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PMID:Withdrawal properties of a neuroactive steroid: implications for GABA(A) receptor gene regulation in the brain and anxiety behavior. 1196 Jun 30

Withdrawal from the endogenous steroid progesterone (P) after chronic administration increases anxiety and seizure susceptibility via declining levels of its potent GABA-modulatory metabolite 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alphaTHP). This 3alpha,5alpha-THP withdrawal also results in a decreased decay time constant for GABA-gated current assessed using whole cell patch-clamp techniques on pyramidal cells acutely dissociated from CA1 hippocampus. The purpose of this study was to test the hypothesis that the decreases in total integrated GABA-gated current observed at the level of the isolated pyramidal cell would be manifested as a reduced GABA inhibition at the circuit level following hormone withdrawal. Toward this end, adult, female rats were administered P via subcutaneous capsule for 3 wk using a multiple withdrawal paradigm. We then evaluated paired-pulse inhibition (PPI) of pyramidal neurons in CA1 hippocampus using extracellular recording techniques in hippocampal slices from rats 24 h after removal of the capsule (P withdrawal, P Wd). The population spike (PS) was recorded at the stratum pyramidale following homosynaptic orthodromic stimulation in the nearby stratum radiatum. The threshold for eliciting a response was decreased after P Wd, and the mean PS amplitude was significantly increased compared with control values at this time. Paired pulses with 10-ms inter-pulse intervals were then applied across an intensity range from 2 to 20 times threshold. Evaluation of paired-pulse responses showed a significant 40-50% reduction in PPI for PS recorded in the hippocampal CA1 region after P Wd, suggesting an increase in circuit excitability. At this time, enhancement of PPI by the benzodiazepine lorazepam (LZM; 10 microM) was prevented, while pentobarbital (10 microM) potentiation of PPI was comparable to control levels of response. These data are consistent with upregulation of the alpha4 subunit of the GABA(A) receptor (GABAR) as we have previously shown. Moreover, the reduced PPI caused by P Wd was prevented by suppression of GABAR alpha4-subunit expression following intraventricular administration of specific antisense oligonucleotides (1 microg/h for 72 h). These results demonstrating a reduction in PPI following P Wd suggest that GABAergic-mediated recurrent or feed-forward inhibition occurring at the circuit level were decreased following P Wd in female rats, an effect at least partially attributable to alterations in the GABAR subunit gene expression.
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PMID:Progesterone withdrawal reduces paired-pulse inhibition in rat hippocampus: dependence on GABA(A) receptor alpha4 subunit upregulation. 1252 71


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