НОВЫЕ ГЕПАТОЛОГИЧЕСКИЕ И НЕВРОЛОГИЧЕСКИЕ КЛИНИЧЕСКИЕ ЭФФЕКТЫ ДЛИННОЦЕПОЧЕЧНЫХ РАСТИТЕЛЬНЫХ ПОЛИПРЕНОЛОВ, ДЕЙСТВУЮЩИИХ НА ПУТЬ ИЗОПРЕНОИДНЫХ МЛЕКОПИТАЮЩИХ

Путь синтеза изопреноидов у млекопитающих (также известный, как мевалонатный путь) является фундаментальным для метаболизма и здоровья организма, а такие соединения, как холестерин (стерольный изопреноид), убихинон (кофермент Q) и долихол (нестерольный изопреноид) имеют огромное значение для биологии и физиологии млекопитающих. Воздействие на путь обмена изопреноидов приводит к новым терапевтическим возможностям, применимым для широкого диапазона различных патологических состояний. Растительные полипренолы являются активными молекулами, которые влияют на путь обмена изопреноидов. При использовании наших полипренолов фармацевтического качества, каковым является Ропрен®, никогда не было зарегистрировано побочных эффектов. Статины и бисфосфонаты также влияют на этот путь обмена, но при этом проявляют множественные побочные эффекты. Наша уникальная возможность производить Ропрен®, содержащий не менее 95% чистых полипренолов, позволила использовать этот препарат в клинической практике в России около 10 лет, а также открыла возможность исследователям проводить клинические испытания для выявления других его терапевтических свойств. Не смотря на то, что полипренолы могут широко применяться для лечения заболеваний, связанных с вирусными, бактериальными и грибковыми инфекциями, воспалениями и другими иммунными состояниями, данная статья представляет новые доклинические и клинические эффекты полипренолов при заболеваниях печени и центральной нервной системы. Недавние доклинические испытания показали, что лечение полипренолами, полученными из хвои, имеет целый ряд неврологических и когнитивных эффектов, включая улучшение когнитивной функции у крыс с заболеванием Альцгеймера и восстановление здорового уровня миелинизации у мышей на модели рассеянного склероза. Более ранние клинические исследования продемонстрировали, что лечение Ропреном® улучшает уровни антиоксидантов у людей с сахарным диабетом, а также улучшает функцию печени у пациентов, проходящих химиотерапию. Ропрен® также оказывает положительное влияние на электроэнцефалограмму у людей с болезнью Альцгеймера и алкогольным циррозом печени и значительно снижает симптомы депрессии у пациентов. Результаты дают основание для проведения более обширных клинических исследований и указывают на то, что Ропрен® является ценным клиническим «инструментом» в лечении целого ряда неврологических и гепатологических заболеваний.

Ропрен, полипренолы, изопреноид, гепатопротектор, неврологические заболевания, мевалонатный путь

1. Adair W. L. Jr., Keller, R. K. Dolichol metabolism in rat liver. Determination of the subcellular distribution of dolichyl phosphate and its site and rate of de novo biosynthesis, J Biol Chem, vol. 257, pp. 8990-8996, 1982.

2. Akula M. K., Shi M, Jiang Z, Foster C. E, Miao D, Li A. S, Zhang X, Gavin R.M, Forde S. D, Germain G, Carpenter S, Rosadini C.V, Gritsman K, Chae J. J, Hampton R, Silverman N, Gravallese E. M, Kagan J. C, Fitzgerald K. A, Kastner D. L, Golenbock D. T, Bergo M. O, Wang D. Control of the innate immune response by the mevalonate pathway, Nat Immunol, vol. 17, no. 8, pp. 922-9, 2016.

3. Bedi O., Dhawan V., Sharma P. L., Kumar P. Pleiotropic effects of statins: new therapeutic targets in drug design, Naunyn-Schmiedeberg’s Arch Pharmacol, vol. 389, pp. 695-712, (2016).

4. Bentinger M., Tekle M., Brismar K., Chojnacki T., Swiezewska E., Dallner G. Polyisoprenoid epoxides stimulate the biosynthesis of coenzyme Q and inhibit cholesterol synthesis, J Biol Chem, vol. 283, pp. 14645-14653, 2008.

5. Bergamini E., Bizzarri R., Cavallini G., Cerbai B., Chiellini E., Donati A., Gori Z., Manfrini A., Parentini I., Signori F., et al. Ageing and oxidative stress: a role for dolichol in the antioxidant machinery of cell membranes?, J Alzheimers Dis, vol 6, pp. 129-135, 2004.

6. Buhaescu I., Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications, Clin Biochem, vol. 40, pp. 575-584, 2007.

7. Burda P., Aebi M. The dolichol pathway of N-linked glycosylation, Biochim Biophys Acta, vol. 1426, pp. 239-257, 1999.

8. Cantagrel V., Lefeber D. J., Ng B. G., Guan Z., Silhavy J. L., Bielas, S. L., Lehle L., Hombauer H., Adamowicz M., Swiezewska E., et al. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder, Cell, vol.142, pp. 203-217, 2010.

9. Cavallini G., Di Stefano R., Bonanomi G., Mosca F., Odetti P., Parentini I., Poggi A., Rossi S., Bergamini E. Changes in dolichol and pentosidine levels in the age-mismatched heterotopically transplanted rat heart, Biogerontology, vol. 5, no. 6, pp. 383-8, 2004.

10. Cavallini G., Sgarbossa A., Parentini I., Bizzarri R., Donati A., Lenci F., Bergamini E. Dolichol: A Component of the Cellular Antioxidant Machinery, Lipids, vol. 51, no. 4, pp. 477-86, 2016.

11. Chojnacki T., Dallner G. The uptake of dietary polyprenols and their modification to active dolichols by the rat liver, J Biol Chem, vol. 258, pp. 916-922, 1983.

12. Chojnacki T., Dallner G. The biological role of dolichol, Biochem J, vol. 251, pp. 1-9, 1988.

13. Ciepichala E., Jemiola-Rzeminskab M., Hertela J., Swiezewskaa E., Strzalkab K. Configuration of polyisoprenoids affects the permeability and thermotropic properties of phospholipid/polyisoprenoid model membranes, Chemistry and Physics of Lipids, vol. 164, pp. 300-306, 2011.

14. Crespo R., Montero Villegas S., Abba M. C., de Bravo M. G., Polo M. P. Transcriptional and posttranscriptional inhibition of HMGCR and PC biosynthesis by geraniol in 2 Hep-G2 cell proliferation linked pathways, Biochem Cell Biol, vol. 91, no. 3, pp. 131-9, 2013.

15. Denecke J., Kranz, C. Hypoglycosylation due to dolichol metabolism defects, Biochim Biophys Acta, vol. 1792, pp. 888-895, 2009.

16. Fedotova J., Soultanov V., Nikitina T., Roschin V., Ordayn N. Ropren(®) is a polyprenol preparation from coniferous plants that ameliorates cognitive deficiency in a rat model of beta-amyloid peptide-(25-35)-induced amnesia, Phytomedicine, vol. 19, no. 5. pp. 451-456, 2012.

17. Fedotova J., Soultanov V., Nikitina T., Roschin V., Ordyan N., Hritcu L. Cognitive-enhancing activities of the polyprenol preparation Ropren® in gonadectomized β-amyloid (25-35) rat model of Alzheimer’s disease, Physiol Behav, vol. 157, pp. 55-62, 2016.

18. Golovanova E. V., Vinnitskaia E. V., Shaposhnikova N. A., Petrakov A. V., Melkina E. S. Effectiveness of the new plant hepatoprotector - Ropren in patients with non-alcoholic steatohepatitis, [Russian] Eksp Klin Gastroenterol, vol. 7, pp. 97-102, 2010.

19. Golovanova E. V., Shaposhnikova N. A., Petrakov A. V., Melkina E. S., Soultanov V. The hepatoprotector Ropren for the treatment of patients with nonalcoholic steatohepatitis: a prospective observational study, Experimental and Clinical Gastroenterology, 2016, in press.

20. Grigor’eva, N. Y., Moiseenkov, A. M. Physiological activity of polyisoprenoids (review of patent data), Pharmaceutical Chemistry Journal, vol. 23, pp. 103-113, 1989.

21. Gruenbacher G., Thurnher M. Mevalonate metabolism in cancer, Cancer Letters, vol. 356, pp. 192-196, 2015.

22. Hartley M. D., Imperiali B. At the membrane frontier: A prospectus on the remarkable evolutionary conservation of polyprenols and polyprenyl-phosphates, Archives of Biochemistry and Biophysics, vol. 517, pp. 83-97, 2012.

23. Hirschberg R. Renal complications from bisphosphonate treatment, Curr Opin Support Palliat Care, vol. 6, no. 3, pp. 342-347, 2012.

24. Hooff G. P., Peters I., Wood W. G., Muller W. E., Eckert, G. P. Modulation of cholesterol, farnesylpyrophosphate, and geranylgeranylpyrophosphate in neuroblastoma SH-SY5Y-APP695 cells: impact on amyloid beta-protein production, Mol Neurobiol, vol. 41, pp. 341-350, 2010a.

25. Hooff G. P., Wood, W. G., Muller, W.E., Eckert, G. P. Isoprenoids, small GTPases and Alzheimer’s disease, Biochim Biophys Acta, vol. 1801, pp. 896-905, 2010b.

26. Husband A. Managing statin-induced myopathy, Clinical Pharmacist, vol. 1, pp. 319-320, 2009.

27. Istvan E. S., Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase, Science, vol. 292, pp. 1160-1164, 2001.

28. Jansone B., Dzirkale Z., Jekabsons K., Pilipenko V., Beitnere U., Magure I., Skumbins R., Kletnieks U., Vanaga I., Muceniece R., Klusa V. Spruce needle polyprenols protect against atorvastatin-induced muscle weakness and do not influence CNS functions in rats, Proc. Latv. Acad. Sci, Section B, vol. 70, pp. 20-30, 2016.

29. Jones P., Kafonek S., Laurora I., Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study), Am J Cardiol, vol. 81, pp. 582-587, 1998.

30. Jones P. H., Davidson M. H., Stein E. A., Bays H. E., McKenney J. M., Miller E., Cain, V. A., Blasetto, J. W. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial), Am J Cardiol, vol.92, pp. 152-160, 2003.

31. Karlsson R., Pedersen E. D., Wang Z., Brakebusch C. Rho GTPase function in tumorigenesis, Biochim Biophys Acta, vol. 1796, 91-98, 2009.

32. Keller R. K., Jehle E., Adair W. L. Jr. The origin of dolichol in the liver of the rat. Determination of the dietary contribution, J Biol Chem, vol. 257, pp. 8985-8989, 1982.

33. Kennel K A., Drake M. T. Adverse effects of bisphosphonates: Implications for osteoporosis management, Mayo Clinic Proceedings, vol. 84, no. 7, pp. 632-638, 2009

34. Khodanovich M., Glazacheva V., Pan E., Akulov A., Krutenkova E., Trusov V., Yarnykh V. MRI study of the cuprizone-induced mouse model of multiple sclerosis: demyelination is not found after co-treatment with polyprenols (long-chain isoprenoid alcohols), Journal of Physics: Conference Series 677 (2016) 012007, doi:10.1088/1742-6596/677/1/012007, 2016.

35. Kirby J., Keasling J. D. Biosynthesis of plant isoprenoids: perspectives for microbial engineering, Annu Rev Plant Biol, vol. 60, pp. 335-355, 2009.

36. Klein-Marcuschamer D., Ajikumar P. K., Stephanopoulos G. Engineering microbial cell factories for biosynthesis of isoprenoid molecules: beyond lycopene. Trends Biotechnol, vol. 25, pp. 417-424, 2007.

37. Lapteva E. N., Roschin V. I., Soultanov V. S. Specific activity of polyprenol- based Ropren in toxic liver damage in a trial [in Russian], Clinical Nutrition, vol. 1, pp. 25-29, 2006.

38. Lapteva E N., Roschin V. I., Soultanov V. S. Specific activity of the polyprenols based therapeutic preparation Ropren (Bioeffective R) in experimental models of toxic liver damage, Clinical Nutrition, vol. 3, pp. 33-37, 2007.

39. Lapteva E. N., Atlas E. E., Popova Yu. R. Differentiated treatment in patients with metabolic syndrome and NASH, XX Russian Congress, Hepatology Today, Russian Journal of Gastroenterology, Hepatology and Coloproctology, no. 1, 2015.

40. Lazarev S. A., Lazareva D. G., Kremleva O. A. Experience of using therapeutic substance Ropren for treatment of hepatic toxicity of the I-II degree during chemotherapy (preliminary results), presented at the Russian scientific-practical conference: “High technology in oncology”, Barnaul, Altay Region, Russia, June 26-27, 2012.

41. Li H., Kuwajima.T, Oakley D., Nikulina E., Hou J., Yang W. S., Lowry E. R., Lamas N. J., Amoroso M. W., Croft G. F., Hosur R., Wichterle H., Sebti S., Filbin M. T., Stockwell B., Henderson C. E. Protein prenylation constitutes an endogenous brake on axonal growth, Cell Reports, vol. 16, no. 2, pp. 545-58, 2016.

42. Li J. W., Vederas, J. C. Drug discovery and natural products: end of an era or an endless frontier?, Science, vol. 325, pp. 161-165, 2009.

43. Marino M, Pallottini V, D’Eramo C, Cavallini G, Bergamini E, Trentalance A. Age-related changes of cholesterol and dolichol biosynthesis in rat liver. Mech Ageing Dev. 2002 Apr 30;123(8):1183-9.

44. Minushkin O. N., Maslovsky L. V., Bukshuk A. A., Arkhipov S. L., Shaposhnikova O. F. Polyprenols: Experience of use of new therapeutic substances in patients with alcohol liver cirrhosis (preliminary data), [in Russian], Kremlin Medicine, vol. 3, pp. 3-5, 2011.

45. Mo H., Elson, C. E. Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention, Exp Biol Med (Maywood), vol. 229, pp. 567-585, 2004.

46. Monakhova I. A., Soultanov V. S., Agishev V. G. Study of the therapuetic properties of Ropren in the treatment of Alzheimer’s type dementia, Abstract presented at the World Psychiatric Assoication regional meeting, St Petersburg, Russia, June 10-12, 2010.

47. Morava E., Wevers R. A., Cantagrel V., Hoefsloot L. H., Al-Gazali L., Schoots J., van Rooij A., Huijben K., van Ravenswaaij-Arts C. M., Jongmans M. C., et al. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism, Brain, vol. 133, pp. 3210-3220, 2010.

48. Muceniece R., Namniece J., Nakurte I., Jekabsons K., Riekstina U., Jansone B. Pharmacological research on natural substances in Latvia: Focus on lunasin, betulin, polyprenol and phlorizin, Pharmacol Res, pii: S1043-6618(16)30007-X, doi: 10.1016/j.phrs.2016.03.040, 2016 Apr 21.

49. Newman D. J., Cragg G. M. Natural Products as sources of new drugs over the 30 years from 1981 to 2010, J Nat Prod, vol. 75, pp. 311-335, 2012.

50. Okeahialam B. N. Reversal of statin-induced memory dysfunction by co-enzyme Q10: a case report, Vasc Health Risk Manag, vol. 11, pp. 579-581, 2015.

51. Parentini I., Bergamini E., Cecchi L., Cavallini G., Donati A., Maccheroni M., Tamburini I., Gorii Z. The effect of carbon tetrachloride and ultraviolet radiation on dolichol levels in liver cells isolated from 3- and 24-month-old male Sprague-Dawley rats, Biogerontology, vol. 4, pp. 365-370, 2003.

52. Parentini I., Cavallini G., Donati A., Gori Z., Bergamini, E. Accumulation of dolichol in older tissues satisfies the proposed criteria to be qualified a biomarker of aging, J Gerontol A Biol Sci Med Sci, vol. 60, pp. 39-43, 2005.

53. Pronin A. V., Danilov L. L., Narovlyansky A. N., Sanin A. V. Plant polyisoprenoids and control of cholesterol level, Arch Immunol Ther Exp (Warsz), vol. 62, no. 1, pp. 31-9, 2014.

54. Roine R., Nykanen I., Salaspuro M. Effect of alcohol on urinary and blood dolichols, Biochem Cell Biol. vol. 70, pp. 404-407, 1992.

55. Roschin V. I., Soultanov V. S. Methods for processing vegetable raw materials. Patent RU2238291, 2003a,

56. Roschin V. I., Soultanov V. S. Preparation for stimulation of natural regeneration of liver. Patent RU2252026, 2003b.

57. Rozman D., Monostory K. Perspectives of the non-statin hypolipidemic agents. Pharmacol Ther, vol. 127, pp. 19-40, 2010.

58. Samaras K., Brodaty H., Sachdev P. S. Does statin use cause memory decline in the elderly?, Trends Cardiovasc Med, vol. 26, no. 6, pp. 550-65, 2016.

59. Silva M., Matthews M. L., Jarvis C., Nolan N. M., Belliveau P., Malloy M., Gandhi, P. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy, Clin Ther, vol. 29, pp. 253-260, 2007.

60. Söderberg M., Edlund C., Kristensson K., Dallner G. Lipid compositions of different regions of the human brain during aging, J Neurochem, vol. 54, no. 2, pp. 415-423, 1990.

61. Söderberg M., Edlund C., Alafuzoff I., Kristensson K., Dallner G. Lipid composition in different regions of the brain in Alzheimer’s disease/senile dementia of Alzheimer’s type, J Neurochem, vol. 59, pp. 1646-1653, 1992.

62. Stough C., Soutanov V. Report: The effect of 90-day chronic administration of a novel pine needle extract (Ropren) on elderly human neuropsychological and cognitive performance, Swinburne University, 2007.

63. Soultanov V. S., Agishev V. G, Monakhova I. A, Mokhovikova I. A., Kulikov A. P., Roschin V. I., Nikitina T. V. Ropren® improves liver and pancreatic function in patients with chronic alcoholism, Gastroenterologica Saint-Petersburg, no. 4, pp. 12-18, 2010.

64. Soultanov V., Fedotova J., Nikitina.T, Roschin V., Ordyan N., Hritcu L. Antidepressant-like effect of Ropren® in β-Amyloid-(25-35) rat model of Alzheimer’s disease with altered levels of androgens, Mol Neurobiol, 2016 Mar 19 [Epub ahead of print].

65. Soultanov V. S., Shabanov P. D, Roschin V. I. Ropren - a first polyprenol pharmaceutical drug in the world for the treatment of diseases of the liver and brain, Pharmaceutical Bulletin, no. 2-3, Kazakhstan, pp. 35-47, 2012.

66. Suraweera C., de Silva V., Hanwella R. Simvastatin-induced cognitive dysfunction: two case reports, J Med Case Rep, 2016 Apr 5;10:83. doi: 10.1186/s13256-016-0877-8.

67. Surmacz L., Swiezewska E., Polyisoprenoids - Secondary metabolites or physiologically important superlipids?, Biochemical and Biophysical Research Communications vol. 407, pp. 627-632, 2011.

68. Sviderskii V. L., Khovanskikh A. E., Rozengart E. V., Moralev S. N., Yagodina, O. V., Gorelkin V. S., Basova I. N., Kormilitsyn B. N., Nikitina T. V., Roshchin V. I., et al. A comparative study of the effect of the polyprenol preparation ropren from coniferous plants on the key enzymes of the cholinergic and monoaminergic types of nervous transmission, Dokl Biochem Biophys, vol. 408, pp. 148-151, 2006.

69. Sviderskii VL., Sultanov VS., Roshchin V. I., Khovanskikh A. E., Rozengart E. V., Moralev, S N., Yagodina O. V., Gorelkina V. S., Kormilitsyn B. N., Basova I. N., et al. Analysis of the effect of the polyprenol preparation ropren and the choline alphoscerate preparation gliatilin on the membrane-bound and soluble forms of cholinesterases and monoamine oxidase of rat brain and serum in the tetrachloromethane model system of hepatic encephalopathy, Dokl Biochem Biophys, vol. 412, pp. 33-36, 2007.

70. Thompson P. D., Panza G., Zaleski A., Taylor B. Statin-associated side effects. J Am Coll Cardiol, vol. 67, no. 20, pp. 2395-2410, 2016.

71. Thurnher M., Gruenbacher G., Nussbaumer O. Regulation of mevalonate metabolism in cancer and immune cells, Biochimica et Biophysica Acta, vol. 1831, pp. 1009-1015, 2013.

72. Tricarico P. M., Kleiner G., Valencic E., Campisciano G., Girardelli M., Crovella S., Knowles A., Marcuzzi A. Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds, International Journal of Molecular Sciences, vol. 15, no. 4, pp. 6843-6856, 2014.

73. Vaĭs E. V., Khyrshkaĭnen T. V., Tursunova N V., Khushbaktova Z. A., Syrov V. N., Kuchin A. V. Pharmacological effects of Abies polyprenols and carsil on alcohol-induced hepatitis, [in Russian] Eksp Klin Farmakol, vol. 75, no. 4, pp. 26-29, 2012.

74. Vajro P., Lenta S., Pignata C., Salerno M., D’aniello R., De Micco I., Paolella G., Parenti. Therapeutic options in pediatric non alcoholic fatty liver disease: current status and future directions, Italian Journal of Pediatrics, vol. 38, p.55, 2012.

75. Wang C., He L., Yan M., Zheng G.Y., Liu X. Y. Effects of polyprenols from pine needles of Pinus massoniana on ameliorating cognitive impairment in a D-galactose-induced mouse model, Age (Dordr), vol. 36, no. 4, p. 9676, 2014.

76. Wang C. Z., Yuan J. J., Li W. J., Zhang H. Y., Ye J. Z. In vivo and in vitro toxicity evaluation of polyprenols extracted from Ginkgo biloba L. leaves, Molecules, vol. 20, no. 12, pp. 22257-22271, 2015.

77. Withers S. T., Keasling, J. D. Biosynthesis and engineering of isoprenoid small molecules, Appl Microbiol Biotechnol, vol. 73, pp. 980-990, 2007.

78. Wood W. G., Gorka C., Schroeder F. Acute and chronic effects of ethanol on transbilayer membrane domains, J Neurochem, vol. 52, pp. 1925-1930, 1989a.

79. Wood W. G., Sun G. Y., Schroeder F. Membrane properties of dolichol in different age groups of mice, Chem Phys Lipids, vol. 51, pp. 219-226, 1989b.

80. Yang L., Wang C. Z., Ye J. Z., et al. Hepatoprotective effects of polyprenols from G. biloba L. leaves on CCl4-induced hepatotoxicityin rats, Fitoterapia, vol. 82, pp. 834-840, 2011.

81. Yu J., Wang Y., Qian H., et al. Polyprenols from Taxus chinensis var. mairei prevent the development of CCl4-induced liver fibrosis in rats, J Ethnopharmacol, vol. 142, pp. 151-160, 2012.

82. Zhang Q., Huang L., Zhang C., Xie P., Zhang Y., Ding S., Xu F. Synthesis and biological activity of polyprenols, Fitoterapia, vol. 106, pp. 184-93, 2015.