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Neuropharmacology. 2017 Apr;116:142-150. doi: 10.1016/j.neuropharm.2016.12.009. Epub 2016 Dec 13.

Effects of the synthetic neurosteroid ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model.

Author information

1
USF Health Byrd Alzheimer's Institute, Tampa, FL, USA; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA.
2
USF Health Byrd Alzheimer's Institute, Tampa, FL, USA.
3
Departments of Neurology and Pharmacology, School of Medicine, University of California, Davis, Sacramento, CA, USA.
4
USF Health Byrd Alzheimer's Institute, Tampa, FL, USA; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA. Electronic address: eweeber@health.usf.edu.

Abstract

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 GABAA receptors could provide therapeutic benefit. Here, we report that ganaxolone, a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, was anxiolytic, anticonvulsant, and improved motor deficits in the Ube3a-deficient mouse model of AS when administered by implanted mini-pump for 3 days or 4 weeks. Treatment for 4 weeks also led to recovery of spatial working memory and hippocampal synaptic plasticity deficits. This study demonstrates that ganaxolone ameliorates many of the behavioral abnormalities in the adult AS mouse, and tolerance did not occur to the therapeutic effects of the drug. The results support clinical studies to investigate ganaxolone as a symptomatic treatment for AS.

KEYWORDS:

Angelman syndrome; Anxiety; GABA; Ganaxolone; Neurosteroid; Seizure

[Indexed for MEDLINE]

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