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

Abstract

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 α5 receptors might be useful in targeting this condition because GABA A α5 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 α5 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 γ-aminobutyric acid at GABA A α5 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 μg) 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

Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging

“…Age-related deficits revealed by this model are associated with disrupted epigenetic regulation in the hippocampus (Castellano et al, 2012), and are sensitive to rescue by pharmacological intervention targeting a variety of mechanisms (Koh et al, 2013;. A pilot study in a small number of aged rats revealed that, consistent with results for exploratory activity in young subjects (Fig.…”

Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

“…As such, despite previous findings that negative modulators improve cognitive function, positive modulators that target α 5 GABA A Rs selectively are being investigated to restore hippocampal activity in aged brains. Using a rat model of age-related memory impairment, two distinct, but non-orally bioavailable, positive modulators of α 5 GABA A Rs, a benzothiophenone (compound 44) and a pyridazine (compound 6) ( Table 1, 2), considerably improved hippocampal-dependent performance tasks, while a negative allosteric modulator had no effect in any of the tasks, further supporting the use of α 5 GABA A R positive modulators in age-related memory impairment [61].…”

“…The loss of neurons in the hippocampus is partly due to the excessive stimulation of the excitatory synaptic glutamatergic receptors, which induces neuronal death [57]. Moreover, in both animal studies and neuroimaging of elderly individuals, age-related memory impairment has been shown to be associated with increased neural activity in the hippocampus [58][59][60][61]. On top of that, the number of inhibitory GABAergic interneurons in the hippocampus was found to be reduced in a mouse model that over-expresses apolipoprotein E4…”

Animal models for Alzheimer’s disease: a focused review of transgenic rodent models and behavioral assessment methods

“…And the results suggested that chronic loss of endothelial nitric oxide might be a crucial contributor to both Aβ related pathology and cognitive deficit [77]. In addition, in the investigation of the effect of GABAA α5 positive allosteric modulators on AD, RAM was used to evaluate the spatial learning and memory capacities change after dosing with these modulators [78]. Furthermore, in the study of the relation between toll-like receptor 9 signalling and AD pathology, RAM was used to test the spatial cognitive function in Tg2576 AD model transgenic mice [79].…”