The Nootropic and Analgesic Effects of Semax Given via Different Routes

The heptapeptide Semax (MEHFPGP) is an analog of the fragment ACTH(4–10) with long-lasting actions. The aim of the present work was to study the effects of Semax on learning ability and pain sensitivity in white rats given different doses via the intraperitoneal and intranasal routes. The nootropic effects of Semax were studied in a test based on the acquisition of a conditioned passive avoidance reaction to pain stimulation. Pain sensitivity was assessed in a hindpaw compression test. The results showed that i.p. Semax had nootropic and analgesic actions. Dose-response characteristics were different for these different effects. Intranasal Semax was more effective in improving learning in animals than i.p. Semax but had no effect on pain sensitivity. Our results provide evidence that different mechanisms and brain structures are involved in mediating the nootropic and analgesic effects of Semax.

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  1. 1.

    I. P. Ashmarin, V. N. Nezavibatko, N. F. Myasoedov, A. A. Kamenskii, I. A. Grivennikov, M. A. Ponomareva-Stepnaya, L. A. Andreeva, A.Ya. Kaplan, V. B. Koshelev, and T. V. Ryasina, “A nootropic analog of adrenocorticotropic hormone 4–10 – Semax,” Zh. Vyssh. Nerv. Deyat., 47, No. 2, 420–430 (1997).

    CAS  Google Scholar 

  2. 2.

    N. Yu. Glazova, E. A. Sebentsova, N. G. Levitskaya, L. A. Andreeva, L. Yu. Alfeeva, A. A. Kamenskii, and N. F. Myasoedov, “Effects of modification of the N-terminal part of the molecule on the extent of the nootropic action of Semax analogs,” Izv. Ros. Akad. Nauk. Ser. Biol., No. 4, 460–466 (2005).

  3. 3.

    D. M. Ivanova, N. G. Levitskaya, L. A. Andreeva, L. Yu. Alfeeva, A. A. Kamenskii, and N. F. Myasoedov, “Effects of Semax on pain sensitivity in animals in various experimental models,” Dokl. Ros. Akad. Nauk., 388, No. 3, 416–419 (2003).

    Google Scholar 

  4. 4.

    D. M. Ivanova, D. A. Vilenskii, N. G. Levitskaya, L. A. Andreeva, L.Yu. Alfeeva, A. A. Kamenskii, and N. F. Myasoedov, “Studies of the relationship between the analgesic activity of melanocortin analogs and their structure,” Izv. Ros. Akad. Nauk. Ser. Biol., No. 2, 162–167 (2006).

    Google Scholar 

  5. 5.

    A. A. Kamenskii, O. G. Voskresenskaya,V. A. Dubynin, and N. G. Levitskaya, “Relationship between the physiological effects of neuropeptides and the route of administration,” Ros. Fiziol. Zh. im. I. M. Sechenova, 87, No. 11, 1493–1501 (2001).

    CAS  Google Scholar 

  6. 6.

    A. A. Kamenskii, N. Yu. Sarycheva, E. Yu. Baturina, and I. P. Ashmarin, “Intranasal administration of regulatory peptides,” Vestn. Akad. Med. Nauk. SSSR, No. 10, 43–47 (1988).

    Google Scholar 

  7. 7.

    A. Ya. Kaplan,V. B. Koshelev,V. N. Nezavibatko, and I. P. Ashmarin, “Increases in the body’s resistance to hypoxia using the neuropeptide medicinal agent Semax,” Fiziol. Cheloveka, 18, No. 5, 104–107 (1992).

    PubMed  CAS  Google Scholar 

  8. 8.

    M. V. Koroleva, E. E. Meizerov,V. N. Nezavibatko, A. A. Kamenskii, V. A. Dubynin, and Y. B. Yakovlev, “Studies of the analgesic action of Semax,” Farmakol. Toksikol., 122, No. 11, 527–529 (1996).

    CAS  Google Scholar 

  9. 9.

    N. G. Levitskaya, E. A. Sebentsova, L. A. Andreeva, L. Yu. Alfeeva, A. A. Kamenskii, and N. F. Myasoedov, “The neuroprotective effects of Semax on the background of MPTP-induced lesions to the brain dopaminergic system,” Ros. Fiziol. Zh. im. I. M. Sechenova, 88, No. 11, 1369–1377 (2002).

    CAS  Google Scholar 

  10. 10.

    M. A. Ponomareva-Stepnaya, V. N. Nezavibatko, L. V. Antonomva, L. A. Andreeva, L. Yu. Alfeeva,V. N. Potaman, A. A. Kamenskii, and I. P. Ashmarin, “A long-acting ACTH4-10 analog which stimulates learning,” Khim.-Farm. Zh., 18, No. 7, 790–795 (1984).

    CAS  Google Scholar 

  11. 11.

    I. P. Ashmarin, V. N. Nezavibatko, N. G. Levitskaya, V. B. Koshelev, and A. A. Kamensky, “Design and investigation of an ACTH(4–10) analogue lacking D-amino acids and hydrophobic radicals,” Neurosci. Res. Commun., 16, No. 2, 105–112 (1995).

    CAS  Google Scholar 

  12. 12.

    J. Born, T. Lange,W. Kern, G. P. McGregor, U. Bickel, and H. L. Fehm, “Sniffing neuropeptides: a transnasal approach to the human brain,” Nat. Neurosci., 5, No. 6, 514–516 (2002).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    X. Q. Chen, J. R. Fawcett,Y. E. Rahman, T. A. Ala, and W. H. Frey, “Delivery of nerve growth factor to the brain via the olfactory pathway,” J. Alzh. Dis., 1, No. 1, 35–44 (1998).

    CAS  Google Scholar 

  14. 14.

    S. V. Dhuria, L. R. Hanson, and W. H. Frey, “Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system,” J. Pharm. Sci., 98, No. 7, 2501–2515 (2009).

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    S. V. Dhuria, L. R. Hanson, and W. H. Frey, “Intranasal delivery to the central nervous system: mechanisms and experimental considerations,” J. Pharm. Sci., 99, No. 4, 1654–1673 (2010).

    PubMed  CAS  Google Scholar 

  16. 16.

    O. V. Dolotov, E. A. Karpenko, L. S. Inozemtseva, T. S. Seredenina, N. G. Levitskaya, J. Rozyczka, E. V. Dubynina, E. V. Novosadova, L. A. Andreeva, L. Yu. Alfeeva, A. A. Kamensky, I. A. Grivennikov, N. F. Myasoedov, and J. Engele, “Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus,” Brain Res., 1117, No. 1, 54–60 (2006).

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    M. Fekete and D. De Wied, “Dose-related facilitation and inhibition of passive avoidance behaviour by the ACTH(4–10) analog (ORG 2766),” Pharmacol. Biochem. Behav., 17, No. 2, 177–182 (1982).

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    H. M. Greven and D. De Wied, “Influence of peptides structurally related to ACTH and MSH on active avoidance in rats. A structureactivity relationship study,” Front. Horm. Res., 4, 140–152 (1977).

    PubMed  CAS  Google Scholar 

  19. 19.

    L. R. Hanson and W. H. Frey, “Strategies for intranasal delivery of therapeutics for the prevention and treatment of neuroAIDS,” J. Neuroimmune Pharm., 2, 81–86 (2007).

    Article  Google Scholar 

  20. 20.

    L. R. Hanson and H. F. Frey, “Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease,” BMC Neurosci., 9, No. 3, S5 (2008).

    PubMed  Article  Google Scholar 

  21. 21.

    A. A. Hussain, “Intranasal drug delivery,” Adv. Drug Deliv. Rev., 29, No. 1–2, 39–49 (1998).

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    L. Illum, “Transport of drugs from nasal cavity to central nervous system,” Eur. J. Pharm. Sci., 11, 1–18 (2000).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    V. N. Potaman, L. V. Antonova,V. A. Dubynin, D. A. Zaitzev, A. A. Kamensky, N. F. Myasoedov, and V. N. Nezavibatko, “Entry of the synthetic ACTH(4-10) analogue into the rat brain following intravenous injection,” Neurosci. Lett., 127, No. 1, 133–138 (1991).

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    S. M. South and M. T. Smith, “Apparent sensitivity of the hotplate latency test for detection of antinociception following intraperitoneal, intravenous or intracerebroventricular M6G administration to rats,” J. Pharmacol. Exp. Ther., 286, No. 3, 1326–1332 (1998).

    PubMed  CAS  Google Scholar 

  25. 25.

    K. Atarowicz and B. Przewlocka, “The role of melanocortins and their receptors in inflammatory processes, nerve regeneration and nociception,” Life Sci., 73, No. 7, 823–847 (2003).

    Article  Google Scholar 

  26. 26.

    R. G. Thorne, C. R. Emory, T. A. Ala, and W. H. Frey, “Quantitative analysis of the olfactory pathway for drug delivery to the brain,” Brain Res., 692, No. 1–2, 278–282 (1995).

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    J. E. C. Wikberg, R. Muceniece, I. Mandrika, P. Prusis, J. Lindblom, C. Post, and A. Skottner, “New aspects on the melanocortins and their receptors,” Pharmacol. Res., 42, No. 5, 393–420 (2000).

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    J. E. Wikberg and F. Mutulis, “Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction,” Nature Rev. Drug Discov., 7, No. 4, 307–323 (2008).

    Article  CAS  Google Scholar 

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Correspondence to N. G. Levitskaya.

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Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 96, No. 10, pp. 1014–1023, October, 2010.

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Manchenko, D.M., Glazova, N.Y., Levitskaya, N.G. et al. The Nootropic and Analgesic Effects of Semax Given via Different Routes. Neurosci Behav Physi 42, 264–270 (2012).

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  • melanocortin
  • Semax
  • learning
  • pain sensitivity
  • intranasal administration
  • rats