Evaluation of the addictive potential of Cortexin® in preclinical studies

DOI: 10.29296/2618723X-2020-04-03

D.A. Abasheva(1), A.V. Kalatanov (1)*, M.N. Karpenko(2), D.V. Kurkin(3), V.M. Klimenko(2), D.A. Bakulin(3), E.I. Morkovin(3), I.S. Ivleva(2), N.S. Pestereva(2), V.A. Maistrenko(2), Е.Е.  Abrosimova(3), N.S. Kovalev(3), M.A. Dubrovin(3)

1joint-stock company "Pharm-holding", 198515, Saint Petersburg, POS. Strelna, Svyazi str., 34, letter A;
2Institute of experimental medicine, 199376, Saint Petersburg, Akad. Pavlova, 12;
3Volgograd state medical University  of the Ministry of health of Russia; 400131, Volgograd, Fallen Fighters square, 1

D.A. Abasheva – http://orcid.org/0000-0002-7107-2306
A.V. Kalatanova – http://orcid.org/0000-0003-2623-6014
M.N. Karpenko – http://orcid.org/0000-0002-1082-0059
D.V. Kurkin – http://orcid.org/0000-0002-1116-3425
V.M. Klimenko – https://orcid.org/0000-0001-9701-4537
D.A. Bakulin – http://orcid.org/0000-0003-4694-3066
E.I. Morkovin – http://orcid.org/0000-0002-7119-3546
I.S. Ivleva – http://orcid.org/0000-0001-7659-5483
N.S. Pestereva – http://orcid.org/0000-0002-3104-8790
V.A. Maistrenko – http://orcid.org/0000-0001-7004-7873
Е.Е. Abrosimova – http://orcid.org/0000-0002-6472-6906
N.S. Kovalev – http://orcid.org/0000-0003-3498-3810
M.A. Dubrovin – http://orcid.org/0000-0003-1903-8589

Е-mail: [email protected]


Keywords: Cortexin® addictive potential rats mice

For citation:

Abasheva D.A., Kalatanova A.V., Karpenko M.N., Kurkin D.V., Klimenko V.M., Bakulin D.A., Morkovin E.I., Ivleva I.S., Pestereva N.S., Maistrenko V.A., Abrosimova Е.Е., Kovalev N.S., Dubrovin M.A. Evaluation of the addictive potential of Cortexin® in preclinical studies. Laboratory Animals for Science. 2020; 4. https://doi.org/10.29296/2618723X-2020-04-03

Abstract

The investigation of a drug’s dependence potential is required as part of preclinical studies for central nervous system active substances. An integrated strategy applied to addictive potential evaluation not only allows regulatory requirements to be satisfied, but also enables a full assessment of the pharmacological dependence development risk, that exists for substances penetrating the blood-brain barrier. The aim of our study was to assess in vivo the addictive potential of the polypeptide drug Cortexin®, which is able to cross the blood-brain barrier. The first part of the addictive potential study showed that the drug did not bind to the opioid, serotonin and dopamine receptors associated with abuse. The present in vivo study included three experiments: the mouse self-administration test, the conditioned place preference test and a chronic withdrawal syndrome modelling in rats. The drug Cortexin® was administered to animals at therapeutic (1 mg/kg/day) and supratherapeutic (3 and 30 mg/kg/day) doses. Either D-mannitol or saline solution was used as a negative control, while ethanol served as a positive control. Following repeated Cortexin® administration at a dose of 1 mg/kg, the animals did not develop place preference to Cortexin® and the animals’ locomotor activity was not altered. In the intravenous self-administration test, the number of infusions was similar to the placebo group at all studied doses. After 14-day Cortexin® administration, the animals did not develop withdrawal symptoms 24 hours after discontinuation of the drug, and the animals’ exploratory or locomotor activity did not change in the open field test 48 hours after discontinuation of the drug. In summary, the preclinical studies results show that Cortexin® does not have addictive or aversive properties. Thus, according to the preclinical findings, the risk of drug dependence development during clinical use of Cortexin® is minimal. Hence, further extensive preclinical testing is not necessary.

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Author Contributions

D.A. Abasheva – writing the original text of the article.

A.V. Kalatanova – writing the original text of the article, the study design, methodology, data processing, discussion of results, editing articles.

M.N. Karpenko – critical revision of the content of the article, study planning, methodology, data processing, discussion of the results, editing the article, collection, analysis or interpretation of study results.

D.V. Kurkin – critical revision of the content of the article, study planning, methodology, data processing, discussion of the results, editing the article, collection, analysis or interpretation of study results.

V.M. Klimenko – critical revision of the content of the article, study planning, methodology, data processing, discussion of the results, editing the article, collection, analysis or interpretation of study results.

D.A. Bakulin – Study planning, methodology, data processing, discussion of results, article editing, collection, analysis or interpretation of work results.

E.I. Morkovin – Research planning, methodology, data processing, discussion of results, article editing, collection, analysis or interpretation of work results.

I.S. Ivleva – collection, analysis or interpretation of study results.

N.S. Pestereva – collection, analysis or interpretation of study results.

V.A. Maistrenko – collection, analysis or interpretation of study results.

Е.Е. Abrosimova – collection, analysis or interpretation of study results.

N.S. Kovalev – collection, analysis or interpretation of study results.

M.A. Dubrovin – collection, analysis or interpretation of study results.

 

Conflict of interest

The authors declare no conflicts of interest.

The study was carried out with the financial support of CJSC Pharm-Holding. The authors confirm the absence of conflicts of interest and their independence in the preparation of the content of the article, revisions of the article and the formation of conclusions.

References

  1. Гуляева Н.В. Молекулярные механизмы действия препаратов, содержащих пептиды мозга: кортексин. Журнал неврологии и психиатрии им. С.С. Корсакова. 2018;118(10):93-96. [Gulyaeva N.V. Molekulyarnye mekhanizmy deistviya preparatov, soderzhashchikh peptidy mozga: korteksin. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2018;118(10):93-96. (In Russ.)].
  2. Гомазков О.А. Кортексин: молекулярные механизмы и мишени нейропротективной активности. Журнал неврологии и психиатрии им. С.С. Корсакова. 2015;115(8):99-104. [Gomazkov O.A. Korteksin: molekulyarnyye mekhanizmy i misheni neyroprotektivnoy aktivnosti. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2015;115(8):99-104. (In Russ.)].
  3. Руководство по доклиническим исследованиям безопасности в целях проведения клинических исследований и регистрации лекарственных препаратов (ЕАЭС) от 26 ноября 2019 [Интернет]. URL: https://www.alta.ru/tamdoc/19kr0202/ (дата обращения: 08.2020).
  4. ГОСТ Р 53434-2009 Принципы надлежащей лабораторной практики, ГОСТ Р от 02 декабря 2009 года №53434-2009 [Интернет]. URL: http://docs.cntd.ru/document/1200075972 (дата обращения: 08.2020).
  5. ГОСТ Р 51000.4-2011 Общие требования к аккредитации испытательных лабораторий, ГОСТ Р от 29 июня 2012 года №51000.4-2011 [Интернет]. URL: http://docs.cntd.ru/document/1200094437 (дата обращения: 08.2020).
  6. Директива Европейского парламента и Совета Европейского Союза 2010/63/ЕС от 22.09.2010 о защите животных, использующихся для научных целей | ГАРАНТ [Интернет]. URL: http://base.garant.ru/70350564/ (дата обращения: 08.2020).
  7. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press (US); 2011/
  8. Sun Y, Chen G, Zhou K, Zhu Y. A Conditioned Place Preference Protocol for Measuring Incubation of Craving in Rats. J. Vis. Exp. 2018 Nov 6;(141).
  9. Экспериментальное доклиническое изучение аддиктивного потенциала фармакологических средств. Методические рекомендации № 2000/112. Звартау Э.Э., Кузьмин А.В., Беспалов А.Ю. Институт фармакологии ПСПбГМУ. [Eksperimental'noye doklinicheskoye izucheniye addiktivnogo potentsiala farmakologicheskikh sredstv. Metodicheskiye rekomendatsii № 2000/112. Zvartau E.E., Kuz'min A.V., Bespalov A.YU. Institut farmakologii PSPbGMU. (In Russ.)].
  10. Uzbay IT, Kayaalp SO. A modified liquid diet of chronic ethanol administration: validation by ethanol withdrawal syndrome in rats. Pharmacol Res. 1995;31(1):37-42.
  11. Jones BC, Ben-Hamida S, de Vasconcelos AP, Kelche C, Lazarus C, Jackisch R, Cassel JCEffects of ethanol and ecstasy on conditioned place preference in the rat. J. Psychopharmacol. 2010; 24(2): 275-279.

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