Role of 2/3-specific GABA-A receptor isoforms in the development of hippocampus kindling epileptogenesis
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abstract
2018 Elsevier Inc. Objective: Subunit-specific positive allosteric modulators (PAMs) of gamma-aminobutyric acid-A (GABA-A) receptors are commonly used to uncover the role of GABA-A receptor isoforms in brain function. Recently, we have designed novel PAMs selective for 2/3 -subunit containing GABA-A receptors ( 2/3 -selective PAMs) that are nonbenzodiazepine site-mediated and do not show an -subunit isoform selectivity, yet exhibit anxiolytic efficacy with reduced potential for sedation, cognitive impairment, and tolerance. In this study, we used three novel 2/3 -selective PAMs (2-261, 2-262, and 10029) with differential 2/3 -subunit potency to identify the role of 2/3 -selective receptor isoforms in limbic epileptogenesis. Methods: Experimental epileptogenesis was induced in mice by daily hippocampus stimulations until each mouse showed generalized (stage 5) seizures. Patch-clamp electrophysiology was used to record GABA-gated currents. Brain levels of 2/3 -selective PAMs were determined for mechanistic correlations. Results: Treatment with the 2/3 -selective PAMs 2-261 (30 mg/kg), 2-262 (10 mg/kg), and 10029 (30 mg/kg), 30 min prior to stimulations, significantly suppressed the rate of development of kindled seizure activity without affecting the afterdischarge (AD) signal, indicating their disease-modifying activity. The 2/3 -selective agents suppressed chemical epileptogenesis in the pentylenetetrazol model. Test doses of these agents were devoid of acute antiseizure activity in the kindling model. Conclusion: These findings demonstrate that 2/3 -selective PAMs can moderately retard experimental epileptogenesis, indicating the protective role of 2/3 -subunit GABA-A receptor isoforms in the development of epilepsy.
