Disease relevance of GANAXOLONE

• The object of these experiments was to ascertain the efficacy of ganaxolone against absence seizures [1].
• Effect of ganaxolone in a rodent model of cerebral hematoma [2].
• Ganaxolone 30 mg/kg did not clearly improve visuospatial learning several weeks after hemorrhage [2].
• PURPOSE: To determine the effects of a newly synthesized epalon, ganaxolone (GNX), on primarily generalized seizures in rats of various ages during development [3].
• Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy [4].

Psychiatry related information on GANAXOLONE

• The ED50 and lower doses of ganaxolone prevented the observed behavioral effects of PTZ as well as its depressant effects on locomotor activity and rearing of mice [5].

High impact information on GANAXOLONE

• Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) is a novel neurosteroid which has anticonvulsant properties in a number of seizure models as well as the ability to enhance function of the gamma-aminobutyric acid-A (GABA(A)) receptor complex via a neurosteroid binding site [1].
• 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 [6].
• RESULTS: 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) [6].
• Exposure of cultured rat cerebellar granule cells to 1 microM ganaxolone for 5 days had no effect on the abundance of mRNAs encoding the alpha1, alpha2, alpha3, alpha4, alpha5, gamma2L, or gamma2S subunits of the GABA(A) receptor [7].
• Changes in GABA(A) receptor gene expression induced by withdrawal of, but not by long-term exposure to, ganaxolone in cultured rat cerebellar granule cells [7].

Biological context of GANAXOLONE

• The pharmacokinetics of ganaxolone were systematically characterized, and adverse events associated with drug use were documented [8].

Anatomical context of GANAXOLONE

• Ganaxolone belongs to a novel class of neuroactive steroids called epalons, which specifically modulate the gamma-aminobutyric acid type A (GABA[A]) receptor in the central nervous system (CNS) [8].
• CONCLUSIONS: Ganaxolone alone or formulated with pharmaceutical-grade excipients is rapidly absorbed from the gastrointestinal tract after oral administration in doses ranging from 50 to 1,500 mg [8].
• Allopregnanolone and ganaxolone increase the firing activity of dorsal raphe nucleus serotonergic neurons in female rats [9].
• Here, we investigate the role of neurosteroid metabolism by using electrophysiological techniques to compare the actions of 5alpha3alpha and its metabolically stable synthetic analog ganaxolone on inhibitory neurotransmission in CA1 and dentate gyrus neurons [10].

Associations of GANAXOLONE with other chemical compounds

• A synthetically derived neuroactive steroid, ganaxolone (3alphahydroxy-3beta-methyl-5alpha-pregnan-20-one), is in phase-II clinical trials for epilepsy [11].

Gene context of GANAXOLONE

• Ganaxolone is an efficacious anticonvulsant agent in a variety of acute seizure models, as well as in electrical and chemical kindling models, and is currently under Phase II clinical investigation for epilepsy [5].
• Thus, synthetic neuroactive steroids, such as ganaxolone, which are orally active and devoid of hormonal side effects, represent a novel treatment strategy for catamenial epilepsy [12].

Analytical, diagnostic and therapeutic context of GANAXOLONE

• RESULTS: We found that ganaxolone 30 mg/kg significantly increased the ED(50) in the bioassay, for a potency ratio of 1.8+/-0.41 compared with vehicle (P<0.05) [2].
• 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 [4].

References