Good news! Are we finally beginning to address more effectively the causes instead of the symptoms in neurodegenerative disorders!
The brain got rhythm, but with age it becomes out of tune! Just kidding!
"... Seeking an alternative treatment option, ... team turned to gamma oscillations – high-frequency brain waves that have been associated with memory and other cognitive processes. These frequencies are often degraded in people with Alzheimer's and previous research has shown that stimulating Alzheimer's patients with auditory, visual or transcranial signals that mimic gamma oscillations led to reduced plaques. Once again though, no cognitive improvements were seen. ...
In mouse tests, that's exactly what happened. When mice that were genetically modified to have Alzheimer's disease were given the compound, their previously poor performance in a maze improved to equal that of healthy mice. ... it only took two weeks of twice daily oral dosing for the improvement to be seen. The researchers also did not notice any visible side effects during the testing phase. ..."
They created a molecular compound called DDL-920 that worked to inhibit the action of the chemical messenger known as GABA, which serves to dampen gamma oscillations in fast-firing structures known as parvalbumin neurons. ...
From the significance and abstract:
"Significance
Wei et al., have studied the subunit composition of γ-aminobutyric acid type A receptors responsible for the tonic inhibition of parvalbumin positive interneurons and identified a small molecule (DDL-920) as a potent, efficacious, and selective negative allosteric modulator of these receptors. DDL-920 increases the power of γ-oscillations following oral administration and remedies the memory impairment of Alzheimer’s disease model mice in the Barnes maze.
Abstract
Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer’s disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1β2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain’s endogenous γ-oscillations through enhancing the function of PV+INs."
Molecule restores cognition and memory in Alzheimer’s disease mouse study
A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice (open access)
Fig. 4 Effects of DDL-920 (10 mg/kg) oral administration with a pipettor on θ- and γ-oscillations recorded in the hippocampi of AD model mice and on their memory test in the Barnes maze.
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