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Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment
Ming Teng Koh1, Sharon Rosenzweig-Lipson, Michela Gallagher
1Department of Psychological and Brain Sciences, Johns Hopkins University, Ames Hall, 3400 North Charles Street, Baltimore, MD 21218, USA. mtkoh@jhu.edu
Neuropharmacology
|June 27, 2012
Summary
Positive allosteric modulators at GABA(A) α5 receptors improved memory in aged rats. Compounds 44 and 6 enhanced hippocampal-dependent memory, suggesting a new approach for cognitive impairment.
Area of Science:
- Neuroscience
- Pharmacology
- Aging Research
Background:
- Excessive hippocampal activity is linked to brain aging and Alzheimer's disease risk.
- GABA(A) α5 receptors modulate tonic inhibition in the hippocampus, making them a potential therapeutic target.
- Previous research on cognitive enhancers focused on inverse agonists, using outdated models.
Purpose of the Study:
- To investigate the efficacy of positive allosteric modulators at GABA(A) α5 receptors for improving memory in aged rats.
- To assess the impact of Compounds 44 and 6 on hippocampal-dependent memory in cognitively impaired aged rats.
Main Methods:
- Two compounds, Compound 44 and Compound 6, were administered to aged rats with cognitive impairment.
- Memory function was evaluated using the water maze and radial arm maze tasks.
- Drug exposure in the brain and in vivo receptor occupancy in the hippocampus were measured.
Main Results:
- Both Compound 44 and Compound 6 significantly improved hippocampal-dependent memory in aged rats.
- Improvements were observed across different task demands and retention intervals.
- Systemic administration showed dose-dependent improvements correlating with brain drug exposure and hippocampal receptor occupancy.
Conclusions:
- Positive allosteric modulation of GABA(A) α5 receptors offers a promising strategy for enhancing memory in aging and related cognitive impairments.
- Compounds 44 and 6 demonstrate potential as therapeutic agents for conditions characterized by excessive hippocampal activity.
- This research supports a novel therapeutic avenue for age-related cognitive decline and Alzheimer's disease risk.
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