How a low dose of diazepam in early Alzheimer’s disease development lowers the decay of neurons

Scientists have found out that a low dose of the tranquilizer diazepam reduces the breakdown of neurons, seen in the development of Alzheimer’s disease. Low doses of diazepam have been shown to enhance spatial learning and memory retention in rats induced with Alzheimer’s disease.

GABA and its role in Alzheimer’s

Alzheimer’s disease (AD) is a common neurodegenerative disorder in which braincells are progressively damaged and die, leading to a loss of memory, thinking skills, and eventually all other brain functions. The loss of memory is induced by an abnormally high production of gamma- aminobutyric acid (GABA), an inhibitory neurotransmitter. GABA plays a role in the communication in the brain, specifically the hippocampus and neocortex, which are associated with spatial memory. High production of GABA leads towards the inhibition of neurotransmission in these parts of the brain.

Diazepam is a GABAA receptor modulator. It is used as a medicine and known to cause sedative and memory impairing effects. Nevertheless, these effects are caused by doses above 1 mg/kg. Recently, researchers Pilipenko and colleagues from the University of Latvia have found that low doses of diazepam (0.05 mg/kg – 1 mg/kg) reduce the decay of neurons in rats induced with AD.

Morris water maze test

To research spatial memory, these researches used the Morris water maze test, a commonly known experiment in neuroscience. In this test, animals are placed inside a round pool filled with water, containing a visible escape platform. Firstly, the animal is trained to find the platform. Secondly, the escape platform is made invisible and the animal is tested to find the same platform. The time spent searching for the platform, which can be recorded by the software Ethovision XT video tracking software, can confirm spatial memory.

During this research, the rats induced with AD displayed difficulty finding the platform. The decay of neurons in the hippocampus, caused by AD, impaired the rat’s spatial memory. Treatment with low doses of diazepam reduced the effects caused by AD, in early development of the disease.

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Open field test

To investigate locomotor activity, the team of Pilipenko also used the open field test. For this test, animals are placed in a round arena for a certain amount of time. The total distance walked and the total time spent in the center zone, which can be recorded by Ethovision XT 11.0 video tracking software, can serve as a unit for locomotor activity.

Rats treated with diazepam would normally be expected to have  reduced locomotor activity due to the tranquilizing effect. However, they found that low doses of diazepam did not influence locomotor activity, nor did induction of AD.

Diazepam and its effect on brain proteins

Alzheimer’s disease is known to cause neuroinflammation and the dysfunction of neurotransmitter systems. The breakdown of neurotransmitter acetylcholine, increased synthesis of GABA, and reduction of synaptic plasticity are all symptoms of AD development, which can be measured through certain protein concentrations in the brain.

Treatment with a low dose of diazepam reduced this so-called protein pathology in rats induced with AD. Analysis of the neocortex and hippocampus revealed that diazepam prevented neuroinflammation, preserved synaptic plasticity, and normalized protein concentrations associated with acetylcholine breakdown and GABA synthesis.

Diazepam in the battle against Alzheimer’s disease

Though these findings show great potential for the treatment of early development of Alzheimer’s disease, the mechanism behind the non-sedative effect of diazepam remains unclear. GABA-receptors play a large role in the development of AD, and other studies found that the effect of other GABA receptor agonists, like muscimol and baclofen, also reduced memory impairments and neuroinflammation caused by the disease.

Though much further research needs to be done, this study shows that treatment with a low dose of diazepam in the early development of the disease can reduce the effects caused by Alzheimer’s. This different application of an existing medicine brings us one step closer in the direction of therapeutics for the disease.

References

• Pilipenko, V., Narbute, K., Pupure, J., Rumaks, J., Jansone, B., & Klusa, V. (2019). Neuroprotective action of diazepam at very low and moderate doses in Alzheimer's disease model rats. Neuropharmacology, 144, 319-326.
• https://www.youtube.com/watch?v=CrJE0XR0Lso
• https://www.youtube.com/watch?v=ot90GJ1usrk