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

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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.

About the authors

Anastasiya V. Nikitina

Kazan State Medical University

Author for correspondence.
Email: namovol@mail.ru
ORCID iD: 0000-0001-6219-6246

Assistant, Depart. of Pharmacology

Russian Federation, Kazan

Irina I. Semina

Kazan State Medical University

Email: seminai@mail.ru
ORCID iD: 0000-0003-3515-0845

D. Sci. (Med.), Prof. Department of Pharmaco­logy; Head, Central Research Laboratory

Russian Federation, Kazan

Dmitry O. Nikitin

Kazan State Medical University

Email: Richard4777@yandex.ru
ORCID iD: 0000-0001-5773-867X

Assistant, Depart. of Pharmacology

Russian Federation, Kazan

Anastasia A. Vivolanec

Kazan State Medical University

Email: vivnastia@gmail.com
ORCID iD: 0000-0001-6793-7939

student

Russian Federation, Kazan

Diana V. Akhmedieva

Kazan State Medical University

Email: adhimaa@yandex.ru
ORCID iD: 0000-0002-7666-0326

student

Russian Federation, Kazan

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Supplementary files

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2. Fig. 1. Structural formulas of the studied compounds

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3. Fig. 2. Experimental design

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4. Fig. 3. Behavior of female and male rats in the valproate model of autism (VMA) in the “Elevated Plus Maze” technique with 7-day administration of the test compounds. On the abscissa — groups of animals: control — group of control rats; VMA — group of rats in VMA without “treatment”; B2 — group of rats in the VMA after administration of compound B2 (21 mg/kg); T8 — group of rats in the VMA after administration of compound T8 (6 mg/kg); C5 — group of rats in the VMA after administration of compound C5 (15 mg/kg). The ordinate axis is the time (s) spent by the rat in “open arms” (OA) (A) or “closed arms” (CA) (B) (an indicator of anxious behavior); *statistically significant differences compared to animals in the control group, p <0.05; **statistically significant differences in relation to animals without treatment (VMA), p <0.05; #trend 0.05


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5. Fig. 4. Behavior of female and male rats in the valproate model of autism (VMA) using the “Burying Balls” technique during 7-day administration of the test compounds. On the abscissa — groups of animals: control — group of control rats; VMA — group of rats in VMA without “treatment”; B2 — group of rats in the VMA after administration of compound B2 (21 mg/kg); T8 — group of rats in the VMA after administration of compound T8 (6 mg/kg); C5 — group of rats in the VMA after administration of compound C5 (15 mg/kg). The ordinate axis shows the number of buried balls (the severity of stereotypic behavior); *statistically significant differences compared to animals in the control group, p <0.05; **statistically significant differences in relation to animals without treatment (VMA), p <0.05

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6. Fig. 5. Behavior of female and male rats in the valproate model of autism (VMA) in the “Extended open field” test after 7-day administration of the test compounds. On the abscissa — groups of animals: control — group of control rats; VMA — group of rats in VMA without “treatment”; B2 — group of rats in the VMA after administration of compound B2 (21 mg/kg); T8 — group of rats in the VMA after administration of compound T8 (6 mg/kg); C5 — group of rats in the VMA after administration of compound C5 (15 mg/kg). The ordinate axis shows the duration of time (s) spent by the animals in the central zone of the model in the third session compared to control animals (an indicator of socialization); *statistically significant differences compared to animals in the control group, p <0.05; **statistically significant differences in relation to animals without treatment (VMA), p <0.05; #trend 0.05


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