Evaluation of the addictive potential of Cortexin® in preclinical studies

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: Anna.Kalatanova@geropharm.com

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.

HER. 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.

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