Publication date: 2019

DOI: 10.1016/j.bbr.2019.112109

The neurodegenerative diseases have a complex pathogenetic mechanism comprising oxidative stress and re-ceptor system dysfunction caused by various damaging factors such as, for example, brain hypoxia. The purposeof this study was to elucidate the influence of hexahydropyrimidine derivatives on learning, memory, and or-ientation and locomotor activities in the passive avoidance (PA) and open field (OF) tests and to evaluate thesecompounds for their potential antihypoxic and antioxidant action on normobaric hypercapnic hypoxia and toxichypoxia models. We demonstrated that compounds1aand1eadministered as a single 100 mg/kg dose (p.o.)one hour before the tests increased the latency time to enter the dark compartment for the first time and reducedthe time spent in the dark compartment on the 2nd, 7th, and 14th days of PAT and increased the number ofsquares crossed and hole-pokings in the OF test. It was also shown that single administration of compounds1aand1e(in 100 mg/kg dose, p.o.) one hour before generation of hypoxia increased the life span of mice undernormobaric hypoxia by 30% (P < 0.05) and, after injection of sodium nitroprusside, they decreased the mal-ondialdehyde (MDA) level and increased the catalase level in the brain of mice. According to molecular dockingresults, compounds1аand1еare bound in the orthosteric active site of M1 muscarinic receptorviasupramo-lecular interactions with a number of functional amino acids.The results indicate that hexahydropyrimidine derivatives have a beneficial effect on the memory, learningprocesses, and orientation and locomotor activities of rats in an unfamiliar environment and exhibit antihypoxicand antioxidant activities under hypoxia in mice. The cognitive enhancement can be mediated by the effect oflead compounds on the M1 muscarinic acetylcholine receptor.

Издатель: Elsevier Science Publishing Company, Inc.

Тип: Article