Preview

Нервно-мышечные болезни

Расширенный поиск

Плейотропный нейропротективный и метаболический эффекты актовегина


https://doi.org/10.17650/2222-8721-2012-0-4-28-35

Полный текст:

Аннотация

В обзоре рассматриваются механизмы действия актовегина в контексте изучения его эффектов на доклиническом уровне и новой концепции фармакологического лечения неврологических расстройств. Актовегин, получаемый при ультрафильтрации крови телят, состоит из более чем 200 биологических субстанций. Препарат используется при широком спектре заболеваний, включая нарушения периферического и мозгового кровообращения, ожоги, плохое заживление ран, радиационные поражения и диабетическую полинейропатию. Актовегин состоит из молекул малого размера, которые находятся в организме в нормальных физиологических условиях, и поэтому исследования их фармакокинетики и фармакодинамики для определения активной субстанции препарата затруднены. Результаты преклинических исследований показали, что актовегин улучшает метаболический баланс путем повышения усвоения глюкозы и потребление кислорода в условиях ишемии. Актовегин также повышает устойчивость к гамма-радиации и стимулирует ранозаживление. В более поздних работах было установлено, что антиоксидантный и антиапоптотический механизмы действия лежат в основе нейропротективных свойств актовегина, подтвержденных в экспериментах на первичных нейронах гиппокампа крыс и стрептозотоцининдуцированной модели диабетической полинейропатии у крыс. Последние данные свидетельствуют о положительном влиянии актовегина на фактор NF-κB, но при этом многие молекулярные и клеточные механизмы его действия остаются неизвестными. В первую очередь это касается влияния актовегина на нейропластичность, нейрогенез и трофическую функцию нервной системы, и данный аспект требует дальнейших исследований. Тем не менее становится очевидным, что мультифакториальная и многокомпонентная природа актовегина определяет его плейотропный нейропротективный механизм действия и клиническую эффективность.

Об авторах

Fausto Machicao
Molecular Genetics and Diagnosis, Department of Internal Medicine IV, Otfried Müller Str. 10, University Hospital, D-72076, Тюбинген, Германия
Россия


Dafin Fior Muresanu
Department of Neurosciences, University of Medicine and Pharmacy «Iuliu Hatieganu», Клуж-Напока, Румыния
Россия


Harald Hundsberger
Medical and Pharmaceutical Biotechnology IMC Krems, University of Applied Sciences Krems, Piaristengasse 1, A-3500, Кремс, Австрия
Россия


Maren Pflüger
Medical and Pharmaceutical Biotechnology IMC Krems, University of Applied Sciences Krems, Piaristengasse 1, A-3500, Кремс, Австрия
Россия


Alla Guekht
Neurology and Rehabilitation, Department of Neurology and Neurosurgery of the Russian State, Москва, Россия
Россия


Список литературы

1. Muresanu DF. Neuromodulation with pleiotropic and multimodal drugs – future approaches to treatment of neurological disorders. Acta Neurochir Suppl 2010;106:291–4.

2. Labiche LA, Grotta JC. Clinical trials for cytoprotection in stroke. NeuroRx Jan. 2004;1(1):46–70.

3. Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: past experience and current developments. Neurotherapeutics 2010 Jan;7(1):115–26.

4. Bornstein NM. Stroke: practical guide for physicians. S. Karger AG; 2009.

5. Muresanu DF. Neuroprotection and neuroplasticity – a holistic approach and future perspectives. J Neurol Sci 2007 Jun 15;257(1–2):38–43.

6. Mochida H, Kikuchi T, Tanaka H, Ikeda A, Fujii Y, Sasamura T, et al. Influence of Actovegin containing infusion solutions on wound healing and function of the intestinal tract in rats. Pharmacol Ther 1989;17:789–97.

7. Schonwald D, Sixt B, Machicao F, Marx E, Haedenkamp G, Bertsch S. Enhanced proliferation of coronary endothelial cells in response to growth factors is synergized by hemodialysate compounds in vitro. Res Exp Med (Berl) 1991;191(4):259–72.

8. Basu SK, Srinivasan MN, Chuttani K, Ghose A. Evaluation of some radioprotectors by the survival study of rats exposed to lethal dose of whole body gamma radiation. J Radiat Res (Tokyo) 1985 Dec;26(4): 395–403.

9. Hegner N. Wirkung eines deproteinisierten Hämoderivates (Actovegin) im induzierten hypovolämischen Schock unter besonderen Berücksichtigung des Energiestoffwechsels. Johannes-Gutenberg Universität Mainz: Institut für Anästhesiologie; 1983.

10. Giarola P. Effects of blood extract on plasma lipids, blood coagulation, fibrinolysis, and platelet aggregation in experimental hypercholesterolemia of rabbits. Arzneim-Forsch 1974;24:925–8.

11. Elmlinger MW, Kriebel M, Ziegler D. Neuroprotective and anti-oxidative effects of the hemodialysate actovegin on primary rat neurons in vitro. Neuromolecular Med 2011 Dec;13(4):266–74.

12. Dieckmann A, Kriebel M, Andriambeloson E, Ziegler D, Elmlinger M. Treatment with Actovegin® improves sensory nerve function and pathology in streptozotocin- diabetic rats via mechanisms involving inhibition of PARP activation. Exp Clin Endocrinol Diabetes 2011 Oct 21;120(3):132–8.

13. Kuninaka T, Senga Y, Senga H, Weiner M. Nature of enhanced mitochondrial oxidative metabolism by a calf blood extract. J Cell Physiol 1991 Jan;146(1):148–55.

14. Buchmayer F, Pleiner J, Elmlinger MW, Lauer G, Nell G, Sitte HH. Actovegin®: a biological drug for more than 5 decades. Wien Med Wochenschr 2011 Feb; 161(3–4):80–8.

15. Bachmann W, Forster H, Mehnert H. Experimental studies in animals on the effect of a protein-free blood extract on the metabolism of glucose. Arzneim-Forsch 1968;18:1023–7.

16. Rao J, Oz G, Seaquist ER. Regulation of cerebral glucose metabolism. Minerva Endocrinol 2006 Jun;31(2):149–58.

17. McEwen BS, Reagan LP. Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol 2004 Apr 19;490(1–3): 13–24.

18. Grillo CA, Piroli GG, Hendry RM, Reagan LP. Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res 2009 Nov 3;1296:35–45.

19. Kobayashi M, Nikami H, Morimatsu M, Saito M. Expression and localization of insulin-regulatable glucose transporter (GLUT4) in rat brain. Neurosci Lett 1996 Aug 2;213(2):103–6.

20. Pardridge WM, Oldendorf WH, Cancilla P, Frank HJ. Blood–brain barrier: interface between internal medicine and the brain. Ann Intern Med 1986 Jul;105(1):82–95.

21. Zhao WQ, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004 Apr 19;490(1–3):71–81.

22. Nitsch R, Hoyer S. Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex. Neurosci Lett 1991 Jul 22;128(2):199–202.

23. Ding A, Nemeth G, Hoyer S. Age influences abnormalities in striatal dopamine metabolism during and after transient forebrain ischemia. J Neural Transm Park Dis Dement Sect 1992;4(3):213–25.

24. Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 1998 Oct;112(5):1199–208.

25. Salkovic-Petrisic M, Hoyer S. Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl 2007;72:217–33.

26. Machicao F, Mühlbacher C, Haring H. Inositol phospho-oligosaccharides from a dialysate (Actovegin) obtained from blood mimic the effect of lipogenesis glucose transport and lipolysis in rat adipocytes. Akt Endokr Stoffw 1989;10:111.

27. Kellerer M, Machicao F, Berti L, Sixt B, Mushack J, Seffer E, et al. Inositol phosphooligosaccharides from rat fibroblasts and adipocytes stimulate 3-O-methylglucose transport. Biochem J 1993 Nov 1;295 (Pt 3):699–704.

28. Reichel H, Weiss C, Leichtweiss HP. The effects of a blood extract on the oxygen uptake of isolated artificially perfused kidneys and skeletal muscles in rats. Arzneim-Forsch 1965;15(756):757.

29. de Groot H, Brecht M, Machicao F. Evidence for a factor protective against hypoxic liver parenchymal cell injury in a protein-free blood extract. Res Commun Chem Pathol Pharmacol Apr. 1990;68(1):125–8.

30. Hoyer S, Betz K. Elimination of the delayed postischemic energy deficit in cerebral cortex and hippocampus of aged rats with a dried, deproteinized blood extract (Actovegin). Arch Gerontol Geriatr 1989 Sep;9(2):181–92.

31. Murakami K, Shimizu T, Irie K. Formation of the 42-mer amyloid beta radical and the therapeutic role of superoxide dismutase in Alzheimer's disease. J Amino Acids 2011;2011:654207.

32. Zhang XH, Yu HL, Xiao R, Xiang L, Li L, Ma WW, et al. Neurotoxicity of betaamyloid peptide 31–35 and 25–35 to cultured rat cortical neurons. Zhonghua Yu Fang Yi Xue Za Zhi 2009 Dec;43(12): 1081–5.

33. Pike CJ, Walencewicz-Wasserman AJ, Kosmoski J, Cribbs DH, Glabe CG, Cotman CW. Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25–35 region to aggregation and neurotoxicity. J Neurochem 1995 Jan;64(1): 253-65.

34. Millucci L, Raggiaschi R, Franceschini D, Terstappen G, Santucci A. Rapid aggregation and assembly in aqueous solution of A beta (25–35) peptide. J Biosci 2009 Jun;34(2):293–303.

35. Trubetskaya VV, Stepanichev MY, Onufriev MV, Lazareva NA, Markevich VA, Gulyaeva NV. Administration of aggregated beta-amyloid peptide (25–35) induces changes in long-term potentiation in the hippocampus in vivo. Neurosci Behav Physiol 2003 Feb;33(2):95–8.

36. Klementiev B, Novikova T, Novitskaya V, Walmod PS, Dmytriyeva O, Pakkenberg B, et al. A neural cell adhesion moleculederived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25–35. Neuroscience 2007 Mar 2; 145(1):209–24.

37. Kubo T, Nishimura S, Kumagae Y, Kaneko I. In vivo conversion of racemized beta-amyloid ([D-Ser 26]A beta 1–40) to truncated and toxic fragments ([D-Ser 26] A beta 25–35/40) and fragment presence in the brains of Alzheimer's patients. J Neurosci Res 2002 Nov 1;70(3):474–83.

38. Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D. NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 2003 Oct;6(10):1072–8.

39. Kaltschmidt B, Kaltschmidt C. NFkappa B in the nervous system. Cold Spring Harb Perspect Biol 2009 Sep;1(3):a001271.

40. Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C. Inhibition of NFkappa B potentiates amyloid beta-mediated neuronal apoptosis. Proc Natl Acad Sci USA 1999 Aug 3;96(16):9409–14.

41. Meunier A, Latremoliere A, Dominguez E, Mauborgne A, Philippe S, Hamon M, et al. Lentiviral-mediated targeted NF-kappa B blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat. Mol Ther 2007 Apr;15(4):687–97.

42. Mattson MP, Meffert MK. Roles for NF-kappa B in nerve cell survival, plasticity, and disease. Cell Death Differ 2006 May;13(5):852–60.

43. Tamatani M, Che YH, Matsuzaki H, Ogawa S, Okado H, Miyake S, et al. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappa B activation in primary hippocampal neurons. J Biol Chem 1999 Mar 26;274(13):8531–8.

44. Kenchappa P, Yadav A, Singh G, Nandana S, Banerjee K. Rescue of TNFalpha-inhibited neuronal cells by IGF-1 involves Akt and c-Jun N-terminal kinases. J Neurosci Res 2004 May 15;76(4):466–74.

45. Waetzig GH, Rosenstiel P, Arlt A, Till A, Brautigam K, Schafer H, et al. Soluble tumor necrosis factor (TNF) receptor-1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factorbeta1. FASEB J 2005 Jan;19(1):91–3.

46. Nawashiro H, Tasaki K, Ruetzler CA, Hallenbeck JM. TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice. J Cereb Blood Flow Metab 1997 May;17(5):483–90.

47. Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 1996 Jul;2(7):788–94.

48. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 2001 Nov;4(11):1116–22.

49. Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J, Mattson MP. Tumor necrosis factors alpha and beta protect neurons against amyloid betapeptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 1995 Sep 26;92(20):9328–32.

50. Kaltschmidt C, Kaltschmidt B, Neumann H, Wekerle H, Baeuerle PA. Constitutive NF-kappa B activity

51. in neurons. Mol Cell Biol 1994 Jun;14(6):3981–92.

52. Pieper AA, Verma A, Zhang J, Snyder SH. Poly (ADP-ribose) polymerase, nitric oxide and cell death. Trends Pharmacol Sci 1999 Apr;20(4):171–81.

53. Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 1997 Oct;3(10):1089–95.

54. Burkart V, Wang ZQ, Radons J, Heller B, Herceg Z, Stingl L, et al. Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin. Nat Med 1999 Mar;5(3):314–9.

55. Pieper AA, Brat DJ, Krug DK, Watkins CC, Gupta A, Blackshaw S, et al. Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocininduced diabetes. Proc Natl Acad Sci USA 1999 Mar 16;96(6):3059–64.

56. Garcia SF, Virag L, Jagtap P, Szabo E, Mabley JG, Liaudet L, et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 2001 Jan;7(1):108–13.

57. Ilnytska O, Lyzogubov VV, Stevens MJ, Drel VR, Mashtalir N, Pacher P, et al. Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy. Diabetes 2006 Jun;55(6): 1686–94.


Для цитирования:


Machicao F., Muresanu D., Hundsberger H., Pflüger M., Guekht A. Плейотропный нейропротективный и метаболический эффекты актовегина. Нервно-мышечные болезни. 2012;(4):28-35. https://doi.org/10.17650/2222-8721-2012-0-4-28-35

For citation:


., ., ., ., . . Neuromuscular Diseases. 2012;(4):28-35. (In Russ.) https://doi.org/10.17650/2222-8721-2012-0-4-28-35

Просмотров: 274


Creative Commons License
Контент доступен под лицензией Creative Commons Attribution 4.0 License.


ISSN 2222-8721 (Print)
ISSN 2413-0443 (Online)