Selective GABAA α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment

NEUROPHARMACOLOGY

卷:64

Article

Koh, Ming Teng¹  Rosenzweig-Lipson, Sharon²  Gallagher, Michela^1,2 

[1] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA

[2] AgeneBio Inc, Carmel, IN 46032 USA

关键词: GABA agonist;    Inverse agonist;    Neural hyperactivity;    Water maze;    Radial arm maze;    Mild cognitive impairment;   

DOI  :  10.1016/j.neuropharm.2012.06.023

来源: Elsevier

【 摘 要 】

A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer's disease. Compounds that act as positive allosteric modulators at GABA(A) alpha 5 receptors might be useful in targeting this condition because GABA(A) alpha 5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABA(A) alpha 5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of gamma-amino-butyric acid at GABA(A) alpha 5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 mu g) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. This article is part of a Special Issue entitled 'Cognitive Enhancers'. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

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