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

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

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.

Full Text

Restricted Access

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

References

  1. Early childhood autism: main symptoms, approaches to correction. Elektronnyy nauchnyy zhurnal VESTNIK “VGPGK”. 2020;(1):46–55. (In Russ.)
  2. Lai MC, Lombardo MV, Auyeung B, Chakrabarti B, Baron-Cohen S. Sex/gender differences and autism: Setting the scene for future research. J Am Acad Child Adolesc Psychiatry. 2015;54(1):11–24. doi: 10.1016/j.jaac.2014.10.003.
  3. Goryacheva TG, Nikitina YuV. Rasstroystva autisticheskogo spektra u detey. Metod sensomotornoy korrektsii. Uchebno-metodicheskoe posobie. (Autism spectrum disorders in children. Method of sensorimotor correction. Teaching aid.) M.: Genesis; 2018. 168 p. (In Russ.)
  4. Cho H, Kim CH, Knight EQ, Oh HW, Park B, Kim DG, Park HJ. Changes in brain metabolic connectivity underlie autistic-like social deficits in a rat model of autism spectrum disorder. Sci Rep. 2017;7(1):13213. doi: 10.1038/s41598-017-13642-3.
  5. Kalinina MA, Kozlovskaya GV, Golubeva NI. Co-treatment with low doses of risperidone and memantine of children autism spectrum disorders. Sovremennaya terapiya v psikhiatrii i nevrologii. 2016;(1):25–29. (In Russ) EDN: VRDDLT.
  6. Semina II, Shilovskaya EV, Tarasova RI, Baichurina AZ, Pavlov VA, Tikhonova NA, Garaev RS. Mechanisms of psychotropic action of phosphorylated carboxylic acid hydrazides. Chemical Pharmaceutical Journal. 2002;36(4):3–6. doi: 10.1023/A:1019807601807.
  7. Semina II, Baychurina AZ. Development of new potential drugs with psychotropic activity among phosphorylacetohydrazides and other phosphorylated carboxylic acids derivatives — priority area of Kazan school of psychopharmacologists. Kazan Medical Journal. 2016;97(1):148–155. (In Russ.) doi: 10.17750/KMJ2016-148.
  8. Semyonova AA, Lopatina OL, Salmina AB. Autism models and assessment techniques for autistic-like behavior in animals. IP Pavlov Journal of Higher Nervous Activity. 2020;70(2):147–162. (In Russ.) doi: 10.31857/S0044467720020112.
  9. Schneider T, Przewłocki R. Behavioral alterations in rats prenatally exposed to valproic acid: Animal model of autism. Neuropsychopharmacology. 2005;30(1):80–89. doi: 10.1038/sj.npp.1300518.
  10. Hisle-Gorman E, Susi A, Stokes T, Gorman G, Erdie-Lalena C, Nylund CM. Prenatal, perinatal, and neonatal risk factors of autism spectrum disorder. Pediatr Res. 2018;84(2):190–198. doi: 10.1038/pr.2018.23.
  11. Mony TJ, Lee JW, Dreyfus C, Di Cicco-Bloom E, Lee HJ. Valproic acid exposure during early postnatal gliogenesis leads to autistic-like behaviors in rats. Clin Psychopharmacol Neurosci. 2016;14(4):338–344. doi: 10.9758/cpn.2016.14.4.338.
  12. Rukovodstvo po provedeniyu doklinicheskikh issledovaniy lekarstvennykh sredstv. Chast' 1. (Guidelines for conducting preclinical studies of drugs. Part 1.) Mironova AN, editor. М.: GrifiK; 2012. 944 p. (In Russ.)
  13. Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc. 2007;2(2):322–328. doi: 10.1038/nprot.2007.44.
  14. Ku KM, Weir RK, Silverman JL, Berman RF, Bauman MD. Behavioral phenotyping of juvenile long-evans and sprague-dawley rats: Implications for preclinical models of autism spectrum disorders. PloS One. 2016;11(6):e0158150. doi: 10.1371/journal.pone.0158150.
  15. Sestakova N, Puzserova A, Kluknavsky M, Bernatova I. Determination of motor activity and anxiety-related behaviour in rodents: Methodological aspects and role of nitric oxide. Interdiscip Toxicol. 2013;6(3):126–135. doi: 10.2478/intox-2013-0020.
  16. Sabatos-DeVito M, Murias M, Dawson G, Howell T, Yuan A, Marsan S, Bernierc RA, Brandt CA, Chawarska K, Dzuira JD, Faja S, Jeste SS, Naples A, Nelsong CA, Shic F, Sugar CA, Webb SJ, McPartland JC. Methodological considerations in the use of Noldus EthoVision XT video tracking of children with autism in multi-site studies. Biol Psychol. 2019;146:107712. doi: 10.1016/j.biopsycho.2019.05.012.
  17. Schneider T, Roman A, Basta-Kaim A, Kubera M, Budziszewska B, Schneider K, Przewłocki R. Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology. 2008;33(6):728–740. doi: 10.1016/j.psyneuen.2008.02.011.
  18. Semina I, Schilovskaya E, Tarasova R, Baychourina A, Pavlov V, Thickhonova N, Garaev R. Mechanism of action of phosphorylacetic acid hydrazides as memory enhancers and neuroptotectors. Phosphorus, Sulfur, and Silicon and the Related Elements. 1999;144(1):753–756. doi: 10.1080/10426509908546354.
  19. Nikitin DO, Nikitina AV, Semina II, Baychurina AZ, Sadykova RG, Ovchinnikova AG, Krutov IA, Gabdrakhmanova DF, Burangulova RN, Gavrilova EL. On the question of the psychotropic properties of new derivatives of phosphorylacethydrazides — salts of arylphosphine acids. Modern problems of science and education. 2019;(3):107. (In Russ.)
  20. Zeidán-Chuliá F, de Oliveira BH, Salmina AB, Casanova MF, Gelain DP, Noda M, Moreira JC. Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients: A model for disrupted brain connectome and therapy. Cell Death Dis. 2014;5(5):e1250. doi: 10.1038/cddis.2014.227.
  21. Nicolini C, Fahnestock M. The valproic acid-induced rodent model of autism. Exp Neurol. 2018;299:217–227. doi: 10.1016/j.expneurol.2017.04.01726.3310.
  22. Kim KC, Kim P, Go HS, Choi CS, Park JH, Kim HJ, Ryu JH. Male specific alteration in excitatory postsynaptic development and social interaction in prenatal valproic acid exposure model of autism spectrum disorder. J Neurochem. 2013;124(6):832–843.
  23. Semina II, Valeeva EV, Nikitin DO, Baichurina AZ, Nikitina AV, Shilovskaya EV, Kravtsova OA. Sex differences in rats in the valproate autism model: disorders in social behavior and changes in Drd1 gene expression in different brain structures. Zhurnal vysshey nervnoy deyatel'nosti im IP Pavlova. 2022;72(6):862–879. (In Russ.) doi: 10.31857/S0044467722060089.
  24. Blackford JU, Pine DS. Neural substrates of childhood anxiety disorders: A review of neuroimaging findings. Child Adolesc Psychiatr Clin N Am. 2012;21(3):501–525. doi: 10.1016/j.chc.2012.05.002.
  25. Carlisi CO, Robinson OJ. The role of prefrontal-subcortical circuitry in negative bias in anxiety: Translational, developmental and treatment perspectives. Brain Neurosci Adv. 2018;2:2398212818774223. doi: 10.1177/2398212818774223.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Structural formulas of the studied compounds

Download (21KB)
Indexing metadata
3. Fig. 2. Experimental design

Download (89KB)
Indexing metadata
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


Download (53KB)
Indexing metadata
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

Download (26KB)
Indexing metadata
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


Download (25KB)
Indexing metadata

© 2024 Eco-Vector




This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies