350 rub
Journal Technologies of Living Systems №1 for 2010 г.
Article in number:
THE DIRECTED SEARCH OF DRUGS FOR THE TREATMENT OF ALZHEIMER DISEASE AND RELATED NEURODEGENERATIVE DISEASES
Keywords: Alzheimer disease drug development mitochondria glutamate receptors
Authors:
S.O. Bachurin, E.F. Shevtsova
Abstract:
The review of the basic approach to the searching for the drugs for treatment of Alzheimer disease and related neurodegenerative diseases is presented. An actual problem is search of multitarget drugs capable both to compensate cognitive deficit and to influence causal factors of neurodege-neration, preventing its development. The strategy of a targets validation for the drugs of new generation - multitarget drugs - is proved on the basis of results of studying of mechanisms of action of Dimebon which now suc-cessfully passing clinical testing. The 6 and 12 months results of Dimebon clinical trials allow to refer it to "illness-modifying" drugs. One of the main mechanisms of cognition enhancing action of Dimebon is ability to influ-ence two subtypes of glutamate receptors. Dimebon exhibited anti-NMDA activity and showed properties of a positive modulator of AMPA-receptors in small concentration. Dimebon proved considerable neuroprotective effect in some cellular models of neurodegeneration. Results available now allow to consider, that mitochondria are the main target of Dimebon as neuroprotective and even as neuroreparative drug that in a combination with it-s cognition enhancing properties caused by a unique profile of interaction with glutamate receptors (NMDA and AMPA) and low tox-icity result in extremely high therapeutic efficiency in Alzheimer's disease clinical trials. Studying of mechanisms of action of Dimebon confirm availability of the targets package and accordingly in vitro screening tests for drugs for treatment БА and related neurodegenerative diseases search developed in our institute.
Pages: 12-18
References
  1. Гаврилова С.И. Болезнь Альцгеймера (деменция альцгеймеровского типа) // Нейродегенеративные болезни и старение. Руководство для врачей / Под ред. И.А. Завалишина, Н.Н. Яхно, С.И. Гавриловой. М. 2001. С. 9-80.
  2. Hudson S., Tabet N.Acetyl-L-carnitine for dementia // Cochrane Database Syst. Rev. 2003. No. 2.
  3. McShane R., Areosa S.A., Minakaran N.Memantine for dementia // Cochrane Database Syst Rev. 2006. No. 2.
  4. Bullock R. Efficacy and Safety of Memantine in Moderate-to-Severe Alzheimer Disease: The Evidence to Date // Alzheimer. Dis. Assoc. Disord. 2006. V. 20. No. 1. P. 23-29.
  5. Воронина Т.А.Новые направления поиска ноотропных препаратов // Вестник РАМН. 2000. № 9. C. 27-34.
  6. Bachurin S.O. Focused Design, Synthesis and Study of  Novel Neuroprotectors and Cognition-Enhancers in Series of Glutamate Receptors Ligands // Drugs of the Future. 2004. V. 29. Suppl. A. P. 296.
  7. LaFerla, F.M., Green, K.N., Oddo, S.Intracellular amyloid-β in Alzheimer's disease // Nature Reviews Neuroscience. 2007. V. 8. No. 7. P. 499-509.
  8. Aisen P.S. The development of anti-amyloid therapy for Alzheimer's disease: from secretase modulators to polymerisation inhibitors // CNS Drugs. 2005. V. 19. No. 12. P. 989-996.
  9. Growdon J.H. Can the immune system fight
    Alzheimer disease - // Nature Medicine. 2006.
    V. 12. No. 7. P. 755.
  10. Schneider A., Mandelkow E. Tau-Based Treatment Strategies in Neurodegenerative Diseases // Neurotherapeutics. 2008. V. 5. No. 3. P. 443-457.
  11. Reddy P.H., Beal M.F. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer-s disease // Trends in Molecular Medicine. 2008. V. 14. No. 2. P. 45-53.
  12. Harman D. Aging: a theory based on free radical and radiation chemistry // J Gerontol. 1956.
    V. 11. No. 3. P. 298-300.
  13. de Grey A.D. A proposed refinement of the mitochondrial free radical theory of aging // Bioessays. 1997. V. 19. P. 161-166.
  14. Gruber J., Schaffer S., Halliwell B. The mitochondrial free radical theory of ageing--where do we stand - // Front Biosci. 2008. V. 13. P. 6554-6579.
  15. Swerdlow R.H. Treating Neurodegeneration by Modifying Mitochondria: Potential Solutions to a "Complex" Problem // Antioxidants & Redox Signaling. 2007. V. 9. No. 10. P. 1591-1604.
  16. Toescu E.C, Verkhratsky A. Ca2+ and mitochondria as substrates for deficits in synaptic plasticity in normal brain ageing // J. Cell. Mol. Med. 2004. V. 8. No. 2. P. 181-190.
  17. Van der Schyf C.J, Mandel S, Youdim MB et al. Novel multifunctional anti-Alzheimer drugs with various CNS neurotransmitter targets and neuroprotective moieties // Curr. Alzheimer. Res. 2007. V. 4. No. 5. P. 522-536.
  18. Editorial article "This unremembered state", The Lancet. 2008. V. 372. P. 177.
  19. Патент (РФ) № 2106864. Средство для лечения болезни Альцгеймера / Н.С. Зефиров, А.З. Афанасьев, С.В. Афанасьева и др.
  20. Doody R., Gavrilova S., Bachurin S., et al.Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study // The Lancet. 2008. V. 372. P. 207-215.
  21. Бачурин С.О., Воронина Т.А., Гарибова Т.Л., Григорьев В.В.Средство, обладающее анксиолитическим действием, на основе гидртрованных пиридо (4,3-b) индолов (варианты), фармакологическое средство на его основе и способ его применения. Решение от 15.04.2008г. о выдаче патента РФ на изобретение по заявке №2007124175 от 28.06.2007
  22. Бачурин С.О., Воронина Т.А., Гарибова Т.Л., Григорьев В.В. Средство для лечения острых и хронических нарушений мозгового кровообращения, в том числе инсульта на основе гидрированных пиридо (4,3-b) индолов (варианты), фармакологическое средство на его основе и способ его применения. Решение от 06.05.2008 г. о выдаче патента РФ на изобретение по заявке №2006143332 от 07.12.2006.

  24. Григорьев В.В., Драный О.А., Бачурин С.О. Сравнительное исследование механизма действия препаратов димебона и мемантина на АМРА- и NMDA-подтипы глутаматных рецепторов нейронов головного мозга крыс // Бюллетень экспериментальной биологии и медицины. 2003. Т. 136. № 11. С. 535-538.
  25. Лермонтова Н.Н., Редкозубов А.Е., Шевцова Е.Ф., Серкова Т.П., Киреева Е.Г., Бачурин С.О. Димебон и такрин ингибируют нейротоксическое действие β-амилоида в культуре и блокируют Са2+-каналы L-типа. // Бюллетень экспе-риментальной биологии и медицины. 2001.
    Т. 132. №11. С.545-550.
  26. Bachurin S.O., Shevtsova E.P., Kireeva E.G., Oxenkrug G.F., Sablin S.O. Mitochondria as a target for neurotoxins and neuroprotective agents // Ann. N.Y. Acad. Sci. 2003. V. 993.
    P.334-344.
  27. Шевцова Е.Ф., Киреева Е.Г., Бачурин С.О. Митохондрии как мишень действия нейропротекторных препаратов // Вестник РАМН. 2005. № 9. C. 13-17.
  28. Hung D. Dimebon: a phase 3 investigational agent for Alzheimer-s disease with a novel mitochondrial mechanism of action // Alzheimer?&Dementia. 2008. V. 4. No. 4. Suppl. 2. P. T182.