An Experimental Evaluation Of Ganaxolone And Its Comparison With Sodium Valproate And Diazepam For Its Sedative Property In Rats

Abstract

Rationale: Ganaxolone (GNX) is the first synthetic analogue of Allopregnanolone. It prevents seizures through positive allosteric modulation of synaptic and extrasynaptic GABA_A receptors, mimicking action of endogenous steroids. The mechanism of action of GNX and sodium valproate are different. Therefore, the two drugs have been combined in our study. Polytherapy (treatment with two or more AEDs) can affect the efficacies in additive, supra-additive (synergistic) or infra-additive manner. Synergistic interactions can be useful because they allow lower doses of each drug to be used, and therefore have the possibility to reduce the side effects.

Objective: To evaluate and compare the sedative effect of ganaxolone, sodium valproate and diazepam on thiopentone sodium induced sleeping time in rats.

Methods: A total of 30 rats were divided into 5 groups, each containing 6 rats for each sedative model. Group 1 was treated with 40% Hydroxypropyl-β-Cyclodextrin i.p, Group 2,3 received GNX 5mg/kg and 10mg/kg i.p respectively, Group 4 was given SV 200 mg/kg i.p and Group 5 was given Diazepam 2mg/kg. Following the i.p. injection of thiopentone sodium, the rats were placed in individual cages and observed for measurements of sleep latency and sleep duration. The duration of drug-induced sleep was measured as the time from the loss (onset) to the recovery of the righting reflex

Results: The mean duration of sleeping time of  ganaxolone 5 mg/kg and sodium valproate 200 mg/kg  was similar to the standard sedative drug diazepam. There was significant difference in the mean duration of sleeping time between ganaxolone 10mg/kg and diazepam 2 mg/kg implying that sedative property of ganaxolone 10 mg/kg was more.

Conclusion:    The sedative effect of ganaxolone  closely match those of  diazepam. Based on this data reported in our study, ganaxolone could be considered a prototypic molecule for a new class of sedative drugs