Role of β 2/3 -specific GABA-A receptor isoforms in the development of hippocampus kindling epileptogenesis

Autor: Doodipala Samba Reddy, Derk J. Hogenkamp, Gunasekaran Ramanathan, Timothy B C Johnstone, Ryan F. Yoshimura, Chase M. Carver, Kelvin W. Gee
Rok vydání: 2018
Předmět:
Zdroj: Epilepsy & Behavior. 82:57-63
ISSN: 1525-5050
DOI: 10.1016/j.yebeh.2018.02.020
Popis: 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 β2/3-subunit containing GABA-A receptors (β2/3-selective PAMs) that are nonbenzodiazepine site-mediated and do not show an α-subunit isoform selectivity, yet exhibit anxiolytic efficacy with reduced potential for sedation, cognitive impairment, and tolerance. In this study, we used three novel β2/3-selective PAMs (2-261, 2-262, and 10029) with differential β2/3-subunit potency to identify the role of β2/3-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 β2/3-selective PAMs were determined for mechanistic correlations. Results Treatment with the β2/3-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 β2/3-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 β2/3-selective PAMs can moderately retard experimental epileptogenesis, indicating the protective role of β2/3-subunit GABA-A receptor isoforms in the development of epilepsy.
Databáze: OpenAIRE
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