The nootropic properties of the tetrapeptide acetyl-(D-lys)-lys-arg-arg-amide (KK-1) on the model of scopolamine-induced alzheimer’s disease in rats

R. D. Deiko, S. Yu. Shtrygol, T. V. Gorbach, O. O. Kolobov, A. S. Simbirtsev

Abstract


Improvement of Alzheimer’s disease (AD) therapy is one of the most important tasks of the modern medicine and pharmacy. Creation and the pharmacological study of the original medicines for treating AD are promising. The most promising class of these drugs is neuroprotectors. In the Research Institute of Highly Pure Biopreparations the tetrapeptide acetyl-(D-Lys)-Lys-Arg-Arg-amide (the laboratory code – KK-1) has been synthesized. Under the conditions of the pre-clinical study it has demonstrated the pronounced neuroprotective and nootropic properties on the model of cerebral ischemia. The aim of the current work is to study the nootropic properties of KK-1 on the model of AD in rats. The scopolamine-induced AD in rats was reproduced. For 10 days the rats with AD model were treated with KK-1 (0.1 mg/kg intranasally once a day) or with the reference medicine donepezil (1 mg/kg orally once a day). After the therapy the functional state of the rats’ CNS was evaluated using the open-field test (OFT), extrapolation escape task (EET) and the test of the conditioned reflex of passive avoidance (CRPA). The level of acetylcholine (Ach) and the activity of acetylcholinesterase (ACE) were measured using spectrophotometry in the whole brain homogenate and brain synaptosoms. The peptide KK-1 studied reduced the stress-related anxiety in OFT in rats, increased their exploratory activity (by 1.4 times, р<0.05 compared to the pathology group) and decreased the emotional response on the stress (by 44%, р<0.05). In EET the tetrapeptide KK-1 stimulated the rats’ cognitive functions, decreased the time of escape by 4.7 times (р<0.05 compared to the pathology group). Under the conditions of the CRPA test the high anti-amnestic activity of KK-1 was found (56.5% on the 1st day after the therapy and 81.5% on the 10th day). According to all indices the activity of KK-1 exceeded the reference medicine donepezil. The mechanism of the KK-1 nootropic action is in the increase of the Ach level in the rats’ brain synaptosoms probably due to stimulation of its synthesis. The peptide KK-1 moderately inhibits the ACE leading also to the Ach level increase in the cholinergic synapse synaptic cleft. It is likely that the peptide KK-1 has an effect on the Gq/G11-peptide-coupled M1-, M3-, and M5-cholinergic receptors as a positive allosteric modulator.


Keywords


Alzheimer’s disease; neuroprotection; melanocortins; tetrapeptide; experiment

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DOI: https://doi.org/10.24959/cphj.16.1406

Abbreviated key title: Klìn. farm.

ISSN 2518-1572 (Online), ISSN 1562-725X (Print)