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Vol. 24, Art. 78 (pp. 1138-1151)    |    2023       

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Influence of oral administration of cyclo-prolyl-alanine on physical activity and cognitive abilities in mammals

Kolobov A.A.1, Aleksandrov G.V.2, Zakharov M.S.2, Kolobov A.A.1

1 Verta LLC, Russian Federation 197110, St. Petersburg, Levashovsky pr., 12, letter A, room 1H, office 307
2 FSUE "State Research Institute of Highly Pure Biopreparations" FMBA of Russia, Russian Federation 197110 St. Petersburg, Pudozhskaya st., 7

Brief summary

Cyclo-prolyl-alanine (CPA) is a natural cyclic dipeptide (2,5-diketopiperazine), widely occurring in many protein-rich foods, including meat, fish, cheese, cocoa, yeast, and many more. Like other diketopiperazines, it is resistant to gastrointestinal enzymes and is absorbed in the intestine. Humans consume up to several milligrams of CPA daily based on their diet. This work describes the effect of CPA on physical activity and cognitive abilities of mammals after oral administration. CPA demonstrated nootropic, actoprotective, and mnemotropic activities. The introduction of CPA accelerated the learning time of rats in the 'open field' non-associative learning test, increased the swimming time of mice and rats in the exercised swimming test, increased the preservation of the memory trace in healthy rats and rats with cerebral ischemia in the test for passive avoidance conditioning (PAC) preservation. CPA was more efficient than a competitive drug No?opept by some parameters. Thus, CPA showed high biological activity after oral administration at concentrations comparable to occurring in food. Given the stimulating effect of CPA, its intake is likely to increase a person's performance or maintain it at the normal level under stress or a lack of natural CPA in food.


Key words

peptide; cyclic peptide; diketopiperazine; nootropic

Reference list

1. Perry T.L., Richardson K.S.C., Hansen S., Friesen A.J.D. Identification of the Diketopiperazine of Histidylproline in Human Urine. J Biol Chem. 1965;240(11):4540-4542.


2. Prasad C. Bioactive cyclic dipeptides. Peptides. 1995;16(1):151-164. doi:10.1016/0196-9781(94)00017-z


3. Stark T., Hofmann T. Structures, sensory activity, and dose/response functions of 2,5-diketopiperazines in roasted cocoa nibs (Theobroma cacao). J Agric Food Chem. 2005;53(18):7222-7231. doi:10.1021/jf051313m


4. Da Costa N.C., Chen M.Z., Merritt D., Trinnaman L. Methionine-Containing Cyclic Dipeptides: Occurrence in Natural Products, Synthesis, and Sensory Evaluation. In: Controlling Maillard Pathways To Generate Flavors. Vol 1042. ACS Symposium Series. American Chemical Society; 2010:111-120. doi:10.1021/bk-2010-1042.ch011


5. Chen M.Z., Dewis M.L., Kraut K., et al. 2, 5-Diketopiperazines (Cyclic Dipeptides) in Beef: Identification, Synthesis, and Sensory Evaluation. J Food Sci. 2009;74(2):C100-C105. doi:10.1111/j.1750-3841.2009.01062.x


6. Shimamura T., Yamamoto K., Otsuka Y. et al. Determination of Cyclic Dipeptides in Extracts of Katsuobushi (Dried Bonito) and Other Dried Fishes. Food Preserv Sci. 2017;43(5):227-233. doi:10.5891/jafps.43.227


7. Otsuka Y. Sakaji M., Arita H. et al. Determination of cyclic dipeptides in various types of cheeses. Milk Sci. 2021;70(2):63-72. doi:10.11465/milk.70.63


8. Yamamoto K., Hayashi M., Murakami Y. et al. Development of LC-MS/MS analysis of cyclic dipeptides and its application to tea extract. Biosci Biotechnol Biochem. 2016;80(1):172-177. doi:10.1080/09168451.2015.1075865


9. Otsuka Y., Shimamura T., Sakaji M. et al. Quantification of Proline-containing Cyclic Dipeptides by LC-MS/MS. Anal Sci. 2020;36(8):977-980. doi:10.2116/analsci.19P470


10. Ginz M., Engelhardt U.H. Identification of new diketopiperazines in roasted coffee. Eur Food Res Technol. 2001;213(1):8-11. doi:10.1007/s002170100322


11. Gautschi M., Schmid J.P., Peppard T.L. et al. Chemical Characterization of Diketopiperazines in Beer. J Agric Food Chem. 1997;45(8):3183-3189. doi:10.1021/jf9700992


12. Chen Y.H., Liou S.E., Chen C.C. Two-step mass spectrometric approach for the identification of diketopiperazines in chicken essence. Eur Food Res Technol. 2004;218(6):589-597.


13. Borthwick A.D., Da Costa N.C. 2,5-diketopiperazines in food and beverages: Taste and bioactivity. Crit Rev Food Sci Nutr. 2017;57(4):718-742. doi:10.1080/10408398.2014.911142


14. Otsuka Y., Arita H., Sakaji M. et al. Investigation of the formation mechanism of proline-containing cyclic dipeptide from the linear peptide. Biosci Biotechnol Biochem. 2019;83(12):2355-2363. doi:10.1080/09168451.2019.1659718


15. Gallo-Torres H.E., Heimer E.P., Witt C. et al. The in vivo gastrointestinal absorption in rats of the intact cyclo(L-leucylglycine) dipeptide. Can J Physiol Pharmacol. 1984;62(3):319-328. doi:10.1139/y84-050


16. Deiko R.D., Shtrigol S.U., Kolobov A.A., Simbircev A.S. Cikloprolilalanin: neiroprotektornie i antioksidantnie svoistva v modeli ostrogo narysheniya mozgovogo krovoobrasheniya y kris. Obzori po klinicheskoi farmakologii i lekarstvennoi terapii. 2016;14(4):16-23. doi:10.17816/RCF14416-23


(Deiko R.D., Shtrygol S.Y., Kolobov A.A., Simbirtsev A.S. Cycloprolylalanine: neuroprotective and antioxidant properties in a model of acute cerebrovascular ishemia in rats. Reviews of clinical pharmacology and drug therapy. 2016;14(4):16-23. doi:10.17816/RCF14416-23)


17. Borthwick A.D., Da Costa N.C. 2,5-diketopiperazines in food and beverages: Taste and bioactivity. Crit Rev Food Sci Nutr. 2017;57(4):718-742. doi:10.1080/10408398.2014.911142


18. Kawai T., Ishida Y., Kakiuchi H. et al. Flavor components of dried squid. J Agric Food Chem. 1991;39(4):770-777. doi:10.1021/jf00004a031


19. Ryan L.A.M., Dal Bello F., Arendt E.K., Koehler P. Detection and quantitation of 2,5-diketopiperazines in wheat sourdough and bread. J Agric Food Chem. 2009;57(20):9563-9568. doi:10.1021/jf902033v