Intravenously Administered Ganaxolone Blocks Diazepam-Resistant Lithium-Pilocarpine–Induced Status Epilepticus in Rats: Comparison with Allopregnanolone

Abstract

Ganaxolone (GNX) is the 3b-methylated synthetic analog of the naturally occurring neurosteroid, allopregnanolone (ALLO). GNX is effective in a broad range of epilepsy and behavioral animal models and is currently in clinical trials designed to assess its anticonvulsant and antidepressant activities. The current studies were designed to broaden the anticonvulsant profile of GNX by evaluating its potential anticonvulsant activities following i.v. administration in treatment-resistant models of status epilepticus (SE), to establish a pharmacokinetic (PK)/pharmacodynamic (PD) relationship, and to compare its PK and anticonvulsant activities to ALLO. In PK studies, GNX had higher exposure levels, a longer halflife, slower clearance, and higher brain penetrance than ALLO. Both GNX and ALLO produced a sedating response as characterized by loss of righting reflex, but neither compound produced a full anesthetic response as animals still responded to painful stimuli. Consistent with their respective PK properties, the sedative effect of GNX was longer than that of ALLO. Unlike other nonanesthetizing anticonvulsant agents indicated for SE, both GNX and ALLO produced anticonvulsant activity in models of pharmacoresistant SE with administration delay times of up to 1 hour after seizure onset. Again, consistent with their respective PK properties, GNX produced a significantly longer anticonvulsant response. These studies show that GNX exhibited improved pharmacological characteristics versus other agents used as treatments for SE and position GNX as a uniquely acting treatment of this indication. These studies were supported by Marinus Pharmaceuticals, Inc.

Augmentation of endogenous neurosteroid synthesis alters experimental status epilepticus dynamics

“…11 For the same molecules, the positive findings were confirmed in the lithium-pilocarpine model of SE. 12 Interestingly, additive properties were also described by combining ganaxolone with tiagabine or midazolam. 13 This further evidence suggests that neurosteroids could be used in polytherapy to address SE.…”

Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells

“…Ganaxolone has been shown to have activity in several animal epilepsy models and is effective in infants with spasm and in adults with partial-onset seizures ( 17 ). Ganaxolone is also potentially useful for treatment of mood and anxiety disorders ( 16 ) and has been shown to improve sociability in a rodent model of autism spectrum disorder, which indicates it may increase sociability in autistic patients ( 26 ). Although ganaxolone can cause sedation in epilepsy patients, few other adverse effects of long-term administration of the drug have been observed to date in clinical trials.…”

“…Although ganaxolone can cause sedation in epilepsy patients, few other adverse effects of long-term administration of the drug have been observed to date in clinical trials. Methylation at the 3β position of ganaxolone impairs its metabolism to inactive metabolites, thereby increasing its period of effectiveness in inhibiting seizures compared to allopregnanolone ( 26 ). Like allopregnanolone, ganaxolone is an allosteric modulator of GABA- A receptors and acts through different allosteric binding sites to that of benzodiazepines, as revealed by ligand binding assays and receptor mutational analysis ( 17 , 27 , 28 ).…”

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

“…17 Allopregnanolone (5α-pregnan-3α-ol-20-one; brexanolone; ALLO), an endogenous neuroactive steroid that acts as an allosteric modulator of both synaptic and extrasynaptic GABA A receptors, has efficacy in diverse seizure models, 18 including models of SE. [19][20][21] The closely related synthetic neuroactive steroid ganaxolone has been shown to be effective in managing seizures induced by DFP and other OPs. 21,22 There is also evidence that ALLO may have antiepileptogenic properties.…”

“…[19][20][21] The closely related synthetic neuroactive steroid ganaxolone has been shown to be effective in managing seizures induced by DFP and other OPs. 21,22 There is also evidence that ALLO may have antiepileptogenic properties. 23,24 Excessive glutamate excitation is a significant mediator of OP SE, and the neuropathology associated with OP poisoning is largely a consequence of glutamatergic excitotoxicity.…”