ganaxolone and Seizures

ganaxolone has been researched along with Seizures* in 22 studies

Reviews

3 review(s) available for ganaxolone and Seizures

ArticleYear
Ganaxolone: First Approval.
    Drugs, 2022, Volume: 82, Issue:8

    Ganaxolone (ZTALMY

    Topics: Adolescent; Anticonvulsants; Child; Clinical Trials, Phase III as Topic; Drug Approval; Humans; Multicenter Studies as Topic; Pregnanolone; Seizures

2022
Neurosteroids: endogenous role in the human brain and therapeutic potentials.
    Progress in brain research, 2010, Volume: 186

    This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful anti-seizure activity in diverse animal models. Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety, and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy, and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.

    Topics: Androstane-3,17-diol; Anesthetics; Anxiety; Brain; Depression; Female; Humans; Male; Neurotransmitter Agents; Pregnanolone; Premenstrual Syndrome; Receptors, GABA-A; Seizures; Sex Characteristics; Stress, Physiological

2010
Catamenial epilepsy: pathophysiology, diagnosis, and management.
    Neurology, 2003, Sep-01, Volume: 61, Issue:6 Suppl 2

    In women with epilepsy, seizures can be influenced by variations in sex hormone secretion during the menstrual cycle. The proconvulsant effects of estrogen have been demonstrated in both animals and humans, whereas progesterone has been found to have anticonvulsant properties. Catamenial epilepsy affects approximately one-third of women with epilepsy. This type of epilepsy has generally been defined as an increase in seizure frequency beginning immediately before or during menses. However, three distinct patterns of catamenial epilepsy have been described: perimenstrual, periovulatory, and luteal. The diagnosis of catamenial epilepsy can be made through careful assessment of menstrual and seizure diaries and characterization of cycle type and duration. A variety of therapies for catamenial epilepsy have been proposed, including acetazolamide, cyclical use of benzodiazepines or conventional antiepileptic drugs (AEDs), and hormonal therapy. However, evidence for the effectiveness of these treatment approaches comes from small, unblinded series or anecdotal reports. Larger multicenter trials, as well as further investigation of the pathophysiology of the disorder, are needed to identify the most effective treatment for women with catamenial epilepsy.

    Topics: Acetazolamide; Adolescent; Adult; Animals; Anticonvulsants; Brain Edema; Bromides; Contraceptives, Oral, Hormonal; Convulsants; Epilepsy; Estradiol; Estrogen Receptor Modulators; Female; Gonadal Steroid Hormones; Humans; Incidence; Menstrual Cycle; Middle Aged; Models, Biological; Periodicity; Potassium Compounds; Pregnanolone; Progesterone; Pyramidal Cells; Rats; Seizures

2003

Trials

3 trial(s) available for ganaxolone and Seizures

ArticleYear
Phase 2, placebo-controlled clinical study of oral ganaxolone in PCDH19-clustering epilepsy.
    Epilepsy research, 2023, Volume: 191

    Protocadherin-19 (PCDH19)-clustering epilepsy is a distinct developmental and epileptic encephalopathy characterized by early-onset seizures that are often treatment refractory. Caused by a mutation of the PCDH19 gene on the X chromosome, this rare epilepsy syndrome primarily affects females with seizure onset commonly in the first year of life. A global, randomized, double-blind, placebo-controlled, phase 2 trial was conducted to evaluate the efficacy, safety, and tolerability of ganaxolone compared with placebo as adjunctive therapy to a standard antiseizure medication regimen in patients with PCDH19-clustering epilepsy (VIOLET; NCT03865732).. Females aged 1-17 years with a molecularly confirmed pathogenic or likely pathogenic PCDH19 variant who were experiencing ≥12 seizures during a 12-week screening period were stratified by baseline allopregnanolone sulfate (Allo-S) levels (low: ≤2.5 ng/mL; high: >2.5 ng/mL) at screening and randomized 1:1 within each strata to receive ganaxolone (maximum daily dose of 63 mg/kg/day if ≤28 kg or 1800 mg/day if >28 kg) or matching placebo in addition to their standard antiseizure treatment for the 17-week double-blind phase. The primary efficacy endpoint was the median percentage change in 28-day seizure frequency from baseline to the 17-week double-blind phase. Treatment-emergent adverse events (TEAEs) were tabulated by overall, system organ class, and preferred term.. Of the 29 patients screened, 21 (median age, 7.0 years; IQR, 5.0-10.0 years) were randomized to receive either ganaxolone (n = 10) or placebo (n = 11). After the 17-week double-blind phase, the median (IQR) percentage change in 28-day seizure frequency from baseline was - 61.5% (-95.9% to -33.4%) among patients in the ganaxolone group and - 24.0% (-88.2% to -4.9%) among patients in the placebo group (Wilcoxon rank-sum test, p = 0.17). TEAEs were reported by 7 of 10 (70.0%) patients in the ganaxolone group and 11 of 11 (100%) patients in the placebo group. Somnolence was the most common TEAE (40.0% ganaxolone vs 27.3% placebo); serious TEAEs were more common in the placebo group (10.0% ganaxolone vs 45.5% placebo); and 1 (10.0%) patient in the ganaxolone group discontinued the study versus none in the placebo group.. Ganaxolone was generally well tolerated and led to a greater reduction in the frequency of PCDH19-clustering seizures compared to placebo; however, the trend did not reach statistical significance. Novel trial designs are likely needed to evaluate the effectiveness of antiseizure treatments for PCDH19-clustering epilepsy.

    Topics: Anticonvulsants; Child; Cluster Analysis; Epilepsy, Generalized; Female; Humans; Pregnanolone; Protocadherins; Seizures; Treatment Outcome

2023
Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial.
    The Lancet. Neurology, 2022, Volume: 21, Issue:5

    CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy.. In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing.. Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase.. Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial.. Marinus Pharmaceuticals.

    Topics: Child; Child, Preschool; Double-Blind Method; Epileptic Syndromes; Humans; Infant; Pregnanolone; Prospective Studies; Protein Serine-Threonine Kinases; Seizures; Spasms, Infantile; Treatment Outcome

2022
Randomized, double-blind, placebo-controlled phase 2 study of ganaxolone as add-on therapy in adults with uncontrolled partial-onset seizures.
    Epilepsia, 2017, Volume: 58, Issue:4

    To evaluate the efficacy and safety of ganaxolone as adjunctive therapy in adults with uncontrolled partial-onset seizures despite taking up to three concomitant antiepileptic drugs (AEDs).. Adults aged 18-69 years and refractory to conventional AEDs were enrolled in a multicenter, double-blind, placebo-controlled trial. After an 8-week baseline period, patients were randomized 2:1 to ganaxolone 1,500 mg/day or placebo for a 10-week treatment period (2-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. The primary endpoint was mean weekly seizure frequency. Secondary endpoints included the proportion of patients experiencing ≥50% reduction in seizure frequency (responder rate), percent change in mean weekly seizure frequency, seizure-free days, and quality of life. Safety and tolerability assessments included adverse events (AEs), treatment discontinuation, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population.. Of 147 randomized patients (98 ganaxolone, 49 placebo), 131 completed the study; 95% of participants titrated up to 1,500 mg/day and 78% maintained this dose. From baseline to endpoint, mean weekly seizure frequency decreased with ganaxolone (6.5-5.2) versus placebo (9.2-10.8), representing an 11.4% decrease versus placebo (p = 0.0489, analysis of covariance [ANCOVA]). Mean percent change from baseline was -17.6% with ganaxolone versus 2.0% with placebo (p = 0.0144, Kruskal-Wallis test). Responder rates were 24% with ganaxolone versus 15% with placebo (p = 0.19). Discontinuation due to adverse events was similar with ganaxolone (7.1%) and placebo (6.1%). Common adverse events were mild to moderate in severity and included dizziness (16.3% vs. 8.2%), fatigue (16.3% vs. 8.2%), and somnolence (13.3% vs. 2.0%).. Ganaxolone 1,500 mg/day reduced partial-onset seizure frequency and was generally safe and well tolerated in this phase 2 study. These results support continued development of ganaxolone for adult patients with refractory partial-onset seizures.

    Topics: Adolescent; Adult; Aged; Analysis of Variance; Anticonvulsants; Double-Blind Method; Female; Humans; Male; Middle Aged; Pregnanolone; Seizures; Treatment Outcome; Young Adult

2017

Other Studies

16 other study(ies) available for ganaxolone and Seizures

ArticleYear
Ganaxolone for management of seizures associated with CDKL5 deficiency disorder.
    Trends in pharmacological sciences, 2023, Volume: 44, Issue:2

    Topics: Epileptic Syndromes; Humans; Protein Serine-Threonine Kinases; Seizures; Spasms, Infantile

2023
Ganaxolone versus Phenobarbital for Neonatal Seizure Management.
    Annals of neurology, 2022, Volume: 92, Issue:6

    Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia.. Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6 hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology.. Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus.. Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.

    Topics: Animals; Animals, Newborn; Anticonvulsants; Asphyxia Neonatorum; Disease Models, Animal; Epilepsy; Humans; Infant, Newborn; Phenobarbital; Pregnanolone; Seizures; Sheep

2022
Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam.
    The Journal of pharmacology and experimental therapeutics, 2020, Volume: 372, Issue:3

    Topics: Animals; Anticonvulsants; beta-Cyclodextrins; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Drug Therapy, Combination; Hippocampus; In Vitro Techniques; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Midazolam; Neurosteroids; Patch-Clamp Techniques; Pregnanolone; Receptors, GABA-A; Seizures; Tiagabine

2020
Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus.
    Neuropharmacology, 2019, Volume: 148

    Zinc is an abundant trace metal in the hippocampus nerve terminals. Previous studies demonstrate the ability of zinc to selectively block neurosteroid-sensitive, extrasynaptic GABA-A receptors in the hippocampus (Carver et al, 2016). Here we report that zinc prevents the seizure protective effects of the synthetic neurosteroid ganaxolone (GX) in an experimental model of epilepsy. GABA-gated and tonic currents were recorded from dissociated dentate gyrus granule cells (DGGCs), CA1 pyramidal cells (CA1PCs), and hippocampal slices from adult mice. Antiseizure effects of GX and the reversal of these effects by zinc were evaluated in fully-kindled mice expressing generalized (stage 5) seizures. In electrophysiological studies, zinc blocked the GABA-evoked and GX-potentiated GABA-gated chloride currents in DGGCs and CA1PCs in a concentration-dependent fashion similar to the competitive GABA-A receptor antagonists bicuculline and gabazine. Zinc completely blocked GX potentiation of extrasynaptic tonic currents, but not synaptic phasic currents. In hippocampus kindling studies, systemic administration of GX produced a dose-dependent suppression of behavioral and electrographic seizures in fully-kindled mice with complete seizure protection at the 10 mg/kg dose. However, the antiseizure effects of GX were significantly prevented by intrahippocampal administration of zinc (ED

    Topics: Animals; Bicuculline; Dose-Response Relationship, Drug; GABA-A Receptor Antagonists; Hippocampus; Kindling, Neurologic; Male; Mice; Microinjections; Neural Inhibition; Neurosteroids; Pregnanolone; Pyridazines; Receptors, GABA-A; Seizures; Zinc

2019
Extrasynaptic γ-aminobutyric acid type A receptor-mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures.
    Epilepsia, 2019, Volume: 60, Issue:4

    Sex differences are evident in the antiseizure activity of neurosteroids; however, the potential mechanisms remain unclear. In this study, we sought to determine whether differences in target extrasynaptic δ-subunit γ-aminobutyric acid type A (GABA-A) receptor expression and function underlie the sex differences in seizure susceptibility and the antiseizure activity of neurosteroids.. Sex differences in seizure susceptibility and protective activity of three distinct neurosteroids-allopregnanolone (AP), androstanediol (AD), and ganaxolone-were evaluated in the pilocarpine model of status epilepticus (SE) and kindling seizure test in mice. Immunocytochemistry was used for δGABA-A receptor expression analysis, and patch-clamp recordings in brain slices evaluated its functional currents.. Sex differences were apparent in kindling epileptogenic seizures, with males exhibiting a faster progression to a fully kindled state. Neurosteroids AP, AD, or ganaxolone produced dose-dependent protection against SE and acute partial seizures. However, female mice exhibited strikingly enhanced sensitivity to the antiseizure activity of neurosteroids compared to males. Sex differences in neurosteroid protection were unrelated to pharmacokinetic factors, as plasma levels of neurosteroids associated with seizure protection were similar between sexes. Mice lacking extrasynaptic δGABA-A receptors did not exhibit sex differences in neurosteroid protection. Consistent with a greater abundance of extrasynaptic δGABA-A receptors, AP produced a significantly greater potentiation of tonic currents in dentate gyrus granule cells in females than males; however, such enhanced AP sensitivity was diminished in δGABA-A receptor knockout female mice.. Neurosteroids exhibit greater antiseizure potency in females than males, likely due to a greater abundance of extrasynaptic δGABA-A receptors that mediate neurosteroid-sensitive tonic currents and seizure protection. These findings indicate the potential to develop personalized gender-specific neurosteroid treatments for SE and epilepsy in men and women, including catamenial epilepsy.

    Topics: Animals; Brain; Female; Male; Mice; Mice, Inbred C57BL; Neurosteroids; Pregnanolone; Receptors, GABA-A; Seizures; Sex Characteristics; Status Epilepticus

2019
3
    The Journal of pharmacology and experimental therapeutics, 2018, Volume: 365, Issue:3

    Neurosteroids are powerful modulators of

    Topics: Allosteric Regulation; Animals; Dentate Gyrus; GABA-A Receptor Antagonists; Ion Channel Gating; Male; Mice; Mice, Inbred C57BL; Neurons; Pregnanolone; Protein Kinase C; Receptors, GABA-A; Seizures; Synapses

2018
Effects of the synthetic neurosteroid ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model.
    Neuropharmacology, 2017, Volume: 116

    Angelman syndrome (AS) is a rare neurogenetic disorder characterized by severe developmental delay, motor impairments, and epilepsy. GABAergic dysfunction is believed to contribute to many of the phenotypic deficits seen in AS. We hypothesized that restoration of inhibitory tone mediated by extrasynaptic GABA

    Topics: Angelman Syndrome; Animals; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Disease Models, Animal; Female; Hippocampus; Long-Term Potentiation; Male; Maze Learning; Memory, Short-Term; Mice, Knockout; Motor Activity; Pentylenetetrazole; Pregnanolone; Receptors, GABA-A; Seizures; Spatial Memory; Tissue Culture Techniques; Ubiquitin-Protein Ligases

2017
Anticonvulsant doses of ganaxolone do not compromise motor performance in immature rats.
    Neuroscience letters, 2010, Jan-29, Volume: 469, Issue:3

    Neuroactive steroids that function as positive modulators of GABA-A receptors are potential anticonvulsant drugs. We previously demonstrated that ganaxolone is effective against pentetrazol-induced motor seizures in immature rats. In the present study, we examined the effects of ganaxolone in another model, cortical epileptic afterdischarges (ADs). The possible side effects of ganaxolone were studied in rats 12, 18, and 25 days of age following the implantation of epidural electrodes. Low-frequency stimulation of the sensorimotor cortical area elicited ADs characterized by a spike-and-wave rhythm and clonic seizures. Ganaxolone (5, 10, 20, or 40 mg/kg) was administered intraperitoneally after the first AD and stimulation was repeated five more times. The highest dose of ganaxolone (40 mg/kg) suppressed progressive prolongation of ADs in 25-day-old rats and postponed it in 12-day-old rats. No significant effect was observed in 18-day-old animals. Movements during stimulation and clonic seizures accompanying ADs were not affected by ganaxolone. Ganaxolone at doses of 20 and 40 mg/kg had no significant effect on motor function, such as surface righting, negative geotaxis, wire mesh ascending, and bar holding. After administration of 40 mg/kg ganaxolone to 18- and 25-day-old rats, spontaneous locomotion in the open field tended to decrease. Doses of ganaxolone with a moderate anticonvulsant effect in the present model did not seriously compromise motor performance.

    Topics: Aging; Animals; Anticonvulsants; Brain; Disease Models, Animal; Electric Stimulation; Epilepsy; Male; Motor Activity; Neuropsychological Tests; Pregnanolone; Rats; Rats, Wistar; Seizures; Time Factors

2010
Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model.
    Epilepsy research, 2010, Volume: 89, Issue:2-3

    Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a synthetic analog of the endogenous neurosteroid allopregnanolone and a positive allosteric modulator of GABAA receptors, may represent a new treatment approach for epilepsy. Here we demonstrate that pretreatment with ganaxolone (1.25-20 mg/kg, s.c.) causes a dose-dependent suppression of behavioral and electrographic seizures in fully amygdala-kindled female mice, with nearly complete seizure protection at the highest dose tested. The ED50 for suppression of behavioral seizures was 6.6 mg/kg. The seizure suppression produced by ganaxolone was comparable to that of clonazepam (ED50, 0.1 mg/kg, s.c.). To the extent that amygdala kindling represents a model of mesial temporal lobe epilepsy, this study supports the utility of ganaxolone in the treatment of patients with temporal lobe seizures.

    Topics: Amygdala; Animals; Anticonvulsants; Clonazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy, Temporal Lobe; Female; Kindling, Neurologic; Mice; Mice, Inbred C57BL; Pregnanolone; Seizures

2010
Allopregnanolone analogs that positively modulate GABA receptors protect against partial seizures induced by 6-Hz electrical stimulation in mice.
    Epilepsia, 2004, Volume: 45, Issue:7

    Low-frequency (6 Hz), long-duration (3 s) electrical stimulation in mice produces seizures characterized by immobility, focal clonus, and automatic behaviors reminiscent of human limbic epilepsy. Renewed interest has been expressed in this seizure model with the recognition that it is sensitive to a broad spectrum of anticonvulsants (AEDs) and may have distinct pharmacologic responsiveness from other in vivo tests of AED efficacy. Here we sought to determine whether the progesterone-derived neuroactive steroid allopregnanolone (5alpha,3alpha-P) and several structural analogues with varying degrees of activity as positive allosteric modulators of gamma-aminobutyric acid (GABA)A receptors are protective in the 6-Hz seizure model.. Mice were pretreated with neuroactive steroids (15 min before) or clonazepam (CZP; 30 min before) to 6-Hz corneal stimulation (32 mA). Animals that failed to exhibit immobility were considered protected.. The neuroactive steroids prevented 6-Hz seizures with rank order of potencies (ED50 values): ganaxolone (6.3 mg/kg) > 5alpha,3alpha-P (14.2 mg/kg) > or = 5beta,3alpha-P (14.4 mg/kg) > 5alpha,3beta-P (>100 mg/kg). CZP also was protective (ED(50) value, 0.075 mg/kg). The potencies of the neuroactive steroids and CZP are similar to their previously reported activities in the pentylenetetrazol (PTZ) seizure model.. Neuroactive steroids have comparable potencies in the 6-Hz and PTZ models. Their structural specificity in both models corresponds with their activities as positive allosteric modulators of GABAA receptors, although ganaxolone is more potent than expected, probably because it has greater bioavailability. The 6-Hz model may be a valuable tool in drug development for the identification of GABAergic AEDs.

    Topics: Animals; Anticonvulsants; Clonazepam; Cornea; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Epilepsies, Partial; GABA Modulators; Humans; Male; Mice; Pregnanolone; Receptors, GABA; Seizures; Steroids

2004
Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.
    European journal of pharmacology, 2003, Aug-08, Volume: 474, Issue:2-3

    Neuroactive steroids demonstrate pharmacological actions that have relevance for a host of neurological and psychiatric disorders. They offer protection against seizures in a range of models and seem to inhibit certain stages of drug dependence in preclinical assessments. The present study was designed to evaluate two endogenous and one synthetic neuroactive steroid that positively modulate the gamma-aminobutyric acid (GABA(A)) receptor against the increase in sensitivity to the convulsant effects of cocaine engendered by repeated cocaine administration (seizure kindling). Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one) and ganaxolone (a synthetic derivative of allopregnanolone 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their ability to suppress the expression (anticonvulsant effect) and development (antiepileptogenic effect) of cocaine-kindled seizures in male, Swiss-Webster mice. Kindled seizures were induced by daily administration of 60 mg/kg cocaine for 5 days. All of these positive GABA(A) modulators suppressed the expression of kindled seizures, whereas only allopregnanolone and ganaxolone inhibited the development of kindling. Allopregnanolone and pregnanolone, but not ganaxolone, also reduced cumulative lethality associated with kindling. These findings demonstrate that some neuroactive steroids attenuate convulsant and sensitizing properties of cocaine and add to a growing literature on their potential use in the modulation of effects of drugs of abuse.

    Topics: Animals; Cocaine; Kindling, Neurologic; Male; Mice; Neuroprotective Agents; Pregnanolone; Seizures

2003
Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate.
    Neuropharmacology, 2000, Apr-27, Volume: 39, Issue:7

    A high-affinity positive modulator of the GABA(A) receptor complex, ganaxolone, is a 3beta-methylated analog of the naturally occurring neuroactive steroid allopregnanolone. In the present study, ganaxolone was tested for its ability to (1) suppress seizures (clonic and tonic) and lethality induced by pentylenetetrazol (PTZ) in PTZ-kindled mice (anticonvulsive effect) and (2) to attenuate the development of sensitization to the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Two classical antiepileptic drugs, diazepam and valproate, were tested for comparison. All three drugs dose-dependently suppressed tonic seizures and lethality induced by PTZ in kindled mice; only ganaxolone was effective against clonic seizures. Ganaxolone showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive (clonic and tonic seizures) and lethal effects of PTZ. Diazepam showed anti-epileptogenic effects against tonic seizures and lethality, but not clonic seizures; valproate was ineffective in preventing development of any of these effects. Sensitivity to PTZ-induced seizures and lethality was not affected in mice with a history of repeated treatment with ganaxolone, diazepam, or valproate. The drugs had effects on ambulatory activity that ranged from no effect (ganaxolone) through moderate impairment (diazepam) to marked disruption (valproate). Taken together, the results of the present study add to accumulating evidence of the unique anticonvulsive/behavioral profile of neuroactive steroids.

    Topics: Animals; Anticonvulsants; Convulsants; Diazepam; Dose-Response Relationship, Drug; Kindling, Neurologic; Male; Mice; Motor Activity; Pentylenetetrazole; Pregnanolone; Seizures; Stereotypic Movement Disorder; Valproic Acid

2000
Effect of ganaxolone on flurothyl seizures in developing rats.
    Epilepsia, 2000, Volume: 41, Issue:7

    To determine the effects of a newly synthesized epalon, ganaxolone (GNX), on primarily generalized seizures in rats of various ages during development. Epalons are classified as neuroactive steroids that interact at unique site of the GABAA receptor-Cl- channel complex in the central nervous system.. Sprague-Dawley male rats were used at 9, 15, 30, and 60 postnatal days (PN). GNX dissolved in 2-hydroxypropylbeta-cyclodextrine was administered intraperitoneally in different doses at various time points before flurothyl testing. The incidence and threshold of clonic and tonic-clonic flurothyl seizures were evaluated. Behavioral changes were also assessed.. In all age groups, the effects of GNX were dose dependent and more prominent 10 min after its administration. In PN 60 and PN 30 rats, GNX had dose-dependent anticonvulsant effects; tonic-clonic seizures were more sensitive to GNX treatment than clonic seizures. In PN 15 and PN 9 rats, GNX demonstrated dose-and time-dependent anticonvulsant effects against both types of flurothyl-induced seizures. GNX was more effective in PN 15 rats than in other age groups, but at doses that altered motor behavior.. GNX has anticonvulsant effects against flurothylinduced seizures in all age groups tested. Its effects are more prominent in the two younger age groups, especially in PN 15 rats, but are associated with motor side effects.

    Topics: Age Factors; Animals; Animals, Newborn; Anticonvulsants; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy, Tonic-Clonic; Flurothyl; Male; Motor Activity; Pregnanolone; Rats; Rats, Sprague-Dawley; Seizures

2000
Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy.
    The Journal of pharmacology and experimental therapeutics, 2000, Volume: 294, Issue:3

    Perimenstrual catamenial epilepsy, the exacerbation of seizures in association with menstruation, may in part be due to withdrawal of the progesterone metabolite allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), an endogenous anticonvulsant neurosteroid that is a positive allosteric modulator of gamma-aminobutyric acid(A) receptors. Neurosteroid replacement is a potential approach to therapy, but natural neurosteroids have poor bioavailability and may be converted to metabolites with undesired progestational activity. The synthetic neuroactive steroid ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnane-20-one) is an orally active analog of allopregnanolone that is not converted to the hormonally active 3-keto form. To assess the potential of ganaxolone in the treatment of catamenial seizure exacerbations, a state of persistently high serum progesterone (pseudopregnancy) was induced in 26-day-old female rats with gonadotropins, and neurosteroids were withdrawn on postnatal day 39 with finasteride, a 5alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone. Finasteride treatment during pseudopregnancy results in a reduction in the threshold for pentylenetetrazol seizures. During this state of enhanced seizure susceptibility, there was a 3-fold increase in the anticonvulsant potency of ganaxolone (control ED(50) = 3.5 mg/kg; withdrawn = 1.2 mg/kg) without a change in the potency for induction of motor toxicity in the rotarod test. The plasma concentrations of ganaxolone did not differ significantly in control and withdrawn animals; the estimated plasma concentrations of ganaxolone producing 50% seizure protection were approximately 500 and approximately 225 ng/ml in control and withdrawn rats, respectively. Unlike ganaxolone, neurosteroid withdrawal was associated with a decrease in the anticonvulsant potency of diazepam (control ED(50) = 1.9 mg/kg; withdrawn = 4.1 mg/kg) and valproate (control ED(50) = 279 mg/kg; withdrawn = 460 mg/kg). The enhanced anticonvulsant potency of ganaxolone after neurosteroid withdrawal supports the use of ganaxolone as a specific treatment for perimenstrual catamenial epilepsy.

    Topics: Animals; Anticonvulsants; Convulsants; Diazepam; Disease Models, Animal; Enzyme Inhibitors; Epilepsy; Female; Finasteride; Menstruation; Oxidoreductases; Pentylenetetrazole; Pregnanolone; Pseudopregnancy; Rats; Rats, Sprague-Dawley; Seizures; Steroids; Valproic Acid

2000
Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor.
    The Journal of pharmacology and experimental therapeutics, 1997, Volume: 280, Issue:3

    Ganaxolone (CCD 1042) is a 3beta-methyl-substituted analog of the endogenous neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one. Ganaxolone inhibited binding of the gamma-aminobutyric acid (GABA)A receptor-chloride channel ligand t-[35S]butylbicyclophosphorothionate (IC50 of 80 nM) and enhanced binding of the benzodiazepine site ligand [3H]flunitrazepam (EC50 of 125 nM) and the GABA site ligand [3H]muscimol (EC50 of 86 nM), consistent with activity as a positive allosteric modulator of the GABA(A) receptor. Electrophysiological recordings showed that, whereas nanomolar concentrations of ganaxolone potentiated GABA-evoked chloride currents in Xenopus oocytes expressing the human GABA(A) receptor subunits alpha1beta1gamma2L, alpha2beta1gamma2L or alpha3beta1gamma2L, direct activation of chloride flux occurred to a limited extent only at micromolar concentrations. Ganaxolone was effective in nontoxic doses against clonic convulsions induced by s.c. pentylenetetrazol administration in mice and rats (ED50 values of 4.3 and 7.8 mg/kg i.p., respectively). Ganaxolone also exhibited potent anticonvulsant activity against seizures induced by s.c. bicuculline (ED50 of 4.6 mg/kg i.p.), i.p. TBPS (ED50 of 11.7 mg/kg i.p.) and i.p. aminophylline (ED50 of 11.5 mg/kg i.p.) in mice. Although ganaxolone effectively blocked tonic seizures induced by maximal electroshock in mice (ED50 of 29.7 mg/kg i.p.), it did so only at doses that produced ataxia on the Rotorod (TD50 of 33.4 mg/kg i.p.). Conversely, ganaxolone was a potent anticonvulsant against fully kindled stage 5 seizures induced by corneal kindling in rats (ED50 of 4.5 mg/kg i.p.), producing these effects at doses well below those that resulted in ataxia (TD50 of 14.2 mg/kg i.p.). The seizure threshold, as determined by an increase in the dose of i.v. infused pentylenetetrazol required to induce clonus, was also significantly elevated by nontoxic doses of ganaxolone in mice. In summary, these data indicate that ganaxolone is a high-affinity, stereoselective, positive allosteric modulator of the GABA(A) receptor complex that exhibits potent anticonvulsant activity across a range of animal procedures. The profile of anticonvulsant activity obtained for ganaxolone supports clinical evaluation of this drug as an antiepileptic therapy with potential utility in the treatment of generalized absence seizures as well as simple and complex partial seizures.

    Topics: Animals; Anticonvulsants; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Flunitrazepam; GABA Modulators; Humans; In Vitro Techniques; Kindling, Neurologic; Mice; Pregnanolone; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Recombinant Proteins; Seizures

1997
Epalons as anticonvulsants: actions mediated by the GABAA receptor complex.
    Proceedings of the Western Pharmacology Society, 1996, Volume: 39

    Topics: Animals; Anticonvulsants; Clinical Trials as Topic; Epilepsy; GABA-A Receptor Agonists; Humans; Pregnanolone; Receptors, GABA-A; Seizures

1996