Objective: The objective of the present study was to test the activity of neurosteroid (NAS) GABAA positive allosteric modulators, including novel synthetic NAS SGE-516, at synaptic and extrasynaptic GABAARs and in a preclinical model of tremor.

Background: GABAA receptors are heteropentameric chloride-conducting ion channels comprised of 5 subunits: two α, two β, and one γ, δ, ρ, θ, π or ε .

Method: Recording of GABA currents in recombinant cells: Modulation of GABA currents by NAS was assessed using recombinant α1β2γ2 (representative synaptic) and α4β3δ (representative extrasynaptic) GABAARs expressed in LTK and CHO cells, respectively. Recording of GABA currents cerebellar slice: Modulation of extrasynaptic (tonic inhibition) and synaptic (phasic inhibition) GABA currents was assessed using whole-cell voltage clamp recordings in rat cerebellar granule cells. Baseline-normalized changes in holding current and inhibitory postsynaptic current decay was measured following application of 0.05, 0.1, and 1 μM of NAS compounds. Measuring harmaline-induced kinetic tremor in mice: Harmaline (10 mg/kg, i.p.) tremor was measured in mice using a piezoelectric (PZ) plate. Vehicle or NAS (0.3, 1, 3 mg/kg, i.p.; n = 15 mice/ group) was administered 30 min prior to harmaline administration. PZ power was measured for 20 min following harmaline administration. Frequency power histograms were constructed and differences between treatment groups were assessed.

Results: NAS SGE-516, positively modulated both synaptic and extrasynaptic GABAA receptors in heterologous cells. Additionally, SGE-516 increased both synaptic and extrasynaptic GABAAR currents in cerebellar granule cells. SGE-516 (1.0 mg/kg, i.p.) led to a significant reduction of peak harmaline response between 10-20Hz (51.5 ± 13.6% (mean ± sem) reduction, p <0.005, one-way ANOVA, Holm-Sidak’s multiple comparison test) and a reduction of PZ power relative to harmaline across time.

Conclusion: NAS SGE-516, is a positive modulator of both synaptic and extrasynaptic GABAARs and is effective in a preclinical model of tremor. By modulating network excitability in a manner distinct from historical GABAergic treatments (e.g. benzodiazepines) it is hypothesized that neurosteroid GABAA receptor modulators may also have a therapeutic potential beyond seizure disorders.

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/activity-of-neurosteroid-gabaa-positive-allosteric-modulators-in-preclinical-harmaline-model-for-essential-tremor/