Study of the effect of phosphorylated carboxylic acids new derivatives on the main behavioral disorders in rats in the valproate model of autism

Abstract

BACKGROUND: Due to the increasing frequency of autism in the population, the complexity of behavioral symptoms, and the need for long-term therapy, it is important to find new safe drugs for the correction of behavioral disorders.

AIM: Studying the possibility of correcting behavioral changes characteristic of autism in rats in the valproate model of autism using new derivatives of phosphorylated carboxylic acids.

MATERIAL AND METHODS: The possibility of correcting behavioral disorders in male and female rats in the valproate model of autism was studied with intraperitoneal administration (7 days) of new derivatives from the group of phosphorylated acetohydrazides (B2, C5) and thiosemicarbazide (T8) in doses of 1/100 LD50 on behavioral tests “Elevated Plus Maze”, “Burying Balls”, “Extended Open Field”. Statistical processing was carried out in the GraphPad prism 8.0.1 program using Student's t-test.

RESULTS: It was found that the most pronounced anxiolytic effect on rats with autism was exerted by the compound 2-[(diphenylphosphoryl)acetyl]-N-phenylhydrazine-1-carbothioamide (T8), increasing by 4.8 times (p=0.033) in females and 4.4 times (p=0.036) in males, the time they spent in open arms in the “Elevated Plus Maze” test. The corrective effect on social behavior in rats with autism was most noted for T8 and B2 [2-ethoxy-2-oxoethanammonium salt (2-ethoxy-2-oxotyl) phenylphosphinic acid], which was characterized by an increase in the time spent with a social object (unfamiliar rat) 6.4 times (p=0.04) and 5.2 times (p=0.039), respectively, in the “Extended open field” method. When assessing the behavior of rats in the valproate model of autism in the “Burying Balls” test, it was found that the use of B2, T8 and C5 reduced the level of stereotypy, reducing the number of buried balls by 1.7 times (p=0.009), 1.5 times (p=0.046 ) and 1.7 times (p=0.011), respectively, compared to rats in the valproate model of autism without treatment.

CONCLUSION: Derivatives of phosphorylated acetohydrazides and thiosemicarbazide have an anxiolytic effect, correct disturbances in social behavior and reduce the severity of stereotypic behavior in rats in the valproate model of autism.

Keywords

phosphorylated acetohydrazide derivatives / valproate model of autism / anxiety / impaired social behavior / stereotypy

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Funding

Исследование выполнено в рамках государственного задания МЗ РФ «Соединения на основе четырёхкоординированного атома фосфора — оптимальная платформа для создания лекарственных препаратов с комплексным механизмом действия для лечения когнитивных нарушений» (2021–2023).The study was carried out within the framework of the state task of the Ministry of Health of the Russian Federation “Compounds based on a four-coordinated phosphorus atom — an optimal platform for the creation of drugs with a complex mechanism of action for the treatment of cognitive impairment” (2021–2023).

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