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21th century drugs. “Magic bullet” or “ Multitarget warhead”

21th century drugs. “Magic bullet” or “ Multitarget warhead”. S.B.Seredenin. The. Paul Ehrlich (1854-1915). The Nobel Prize in Physiology or Medicine 1908 "in recognition of their work on immunity”. Paul Ehrlich 1/2 of the prize Germany Goettingen University Goettingen, Germany;

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21th century drugs. “Magic bullet” or “ Multitarget warhead”

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  1. 21th century drugs.“Magic bullet” or “Multitarget warhead” S.B.Seredenin State Zakusov Institute of Pharmacology RAMS, Moscow

  2. The Paul Ehrlich (1854-1915) The Nobel Prize in Physiology or Medicine 1908 "in recognition of their work on immunity” Paul Ehrlich 1/2 of the prize Germany Goettingen University Goettingen, Germany; Königliches Institut für experimentelle Therapie (Royal Institute for Experimental Therapy) Frankfurt-on-the-Main, Germany Ilya Ilyich Mechnikov 1/2 of the prize Russia Institut Pasteur Paris, France

  3. Схема четырех основных сигнальных механизмов

  4. Afobazol Регистрационный номер: ЛС-000861 от 03.11.2005 State Zakusov Institute of Pharmacology RAMS, Moscow

  5. Effectofemotionalstressonthe3H-diazepam bindinglevel in thebrainmembranesofBalb/c & C57Bl/6 mice Balb/c C57Bl/6 Effectofemotionalstressonthe3H-diazepam bindinglevel in thebrainmembranesof MR & MNRA rats * MNRA MR * State Zakusov Institute of Pharmacology RAMS, Moscow * - р<0.05

  6. EffectofAfobazolon3H-diazepam bindinglevelinthebrainmembranes ofBalb/c& C57Bl/6mice C57Bl/6 Balb/c * EffectofAfobazolon3H-diazepam bindinglevelinthebrainmembranes of MR & MNRA rats MNRA MR * * State Zakusov Institute of Pharmacology RAMS, Moscow * - р<0.05

  7. Протокол нейрорецепторного исследования Афобазола (CEREP, France)

  8. Протокол нейрорецепторного исследования Афобазола(CEREP, France)

  9. Протокол нейрорецепторного исследования Афобазола(CEREP, France)

  10. K+ NMDA R PLC Voltage-gated Ca channel K+ channel Ca + + Ca ATPase PIP2 Ca + + Ca + + DHEA Ca IP3 Ca Ca Ca DAG PKC Calmodulin IP3R Ca Ca Ca Ca IP3 Ca Ca Ca CaM-PK Ca Ca IP3 σ receptor IP3 receptor Cell Effects Ankyrin Lipid raft BiP State Zakusov Institute of Pharmacology RAMS, Moscow

  11. 3H-diazepam biding [Melatonin] MT1 R GABA A R Cl- Afobazol 3H-diazepam biding Cl- - Melatonin - Afobazol State Zakusov Institute of Pharmacology RAMS, Moscow

  12. Immunofluorescence staining Influence of Afobazol on localization of sigma-receptors in HT-22 cell line Control (Localization on endoplasmatic reticulum) Afobazol (10-8М)(Localization on plasma membrane in 60 min following Afobazol application) sigma-receptors Calnexin Sigma-receptor + Calnexin State Zakusov Institute of Pharmacology RAMS, Moscow

  13. Neuroprotective effect of Afobazol in HT-22 cell line exposed to oxidative stress Application 30 min before H2O2 Application 24 h after H2O2 Optical density ControlН2О2 10-8 М 10-5 М 1,5 мМ Optical density Applicationright after H2O2 ControlН2О2 10-8 М 10-5 М 1,5 мМ Optical density State Zakusov Institute of Pharmacology RAMS, Moscow Control Н2О2 10-8 М 10-5 М 1,5 мМ

  14. Protective effect of the Afobazol against glutamate toxicity in hippocampal cell culture HT-22 (MTT assay) After glutamate 24 h before glutamate Afobazol (10-8 М) Afobazol 1 16 24h Control glutamate 5mM Control glutamate 5mM 10-5 M 10-8 M Afobazol was able to prevent cell damage in concentrations which were defined in brain after systemic administration State Zakusov Institute of Pharmacology RAMS, Moscow

  15. Increase in Nerve growth factor (NGF) content 6 hours followingAfobazol(10-8 М) application Western blot analysis NGF 1 2 3 4 5 6 7 Control Afobazol NGF (10-8 М) * Densitometric analysis of the above Western blot Densitometric units Control Afobazol State Zakusov Institute of Pharmacology RAMS, Moscow

  16. Concentration-dependent effect of Afobazol upon BDNF content in hippocampal cell line НТ-22 10-8 10-5 10-10 10-9 10-6 C 10-7 10-11 State Zakusov Institute of Pharmacology RAMS, Moscow

  17. Size of the brain infarct zone after the middle cerebral artery occlusion in rats ** ** Control 1,0 mg/kg 0,1 mg/kg 0,05 mg/kg Afobazol State Zakusov Institute of Pharmacology RAMS, Moscow

  18. Afobazol increase survival following the hemorrhagic stroke in rats State Zakusov Institute of Pharmacology RAMS, Moscow

  19. Effect of Afobazol on the severity of neurological deficits in rats after hemorrhagic stroke (McGrow’s scale) 1 - Flabbiness, motor slowing 2 – weakness in extremities 3 – “manege” locomotion 4 – paresis of 1-4 extremities State Zakusov Institute of Pharmacology RAMS, Moscow

  20. Ladasten Регистрационный номер: № ЛСР-010257/08 State Zakusov Institute of Pharmacology RAMS, Moscow

  21. Фармакологические свойства Ладастена • Мягкое психостимулирующее • Анксиолитическое • Иммуностимулирующее State Zakusov Institute of Pharmacology RAMS, Moscow

  22. Протокол нейрорецепторного исследования Ладастена (CEREP, France)

  23. Протокол нейрорецепторного исследования Ладастена(CEREP, France)

  24. Протокол нейрорецепторного исследования Ладастена(CEREP, France)

  25. Genes and proteins regulated by Ladasten GAPDH NSE PLP  tubulin B  actine alpha  NCAM  PKCIP  PMCA  noggin  gro  bHIH  cell-cycle-progression related protein  APC  Rb  hypocretine  CARB H  galaninr receptor 3  RAB7  synapsins 1A&1B rEXO70  rabphilin3А  CPG2  GAT3  aldolase A  GAPDH  clathrin LCA  tubulin alpha 6  alpha internexin  CRMP-2 neuronal protein 22  Hsp70  CCTe VCP  proteosoma 26S  State Zakusov Institute of Pharmacology RAMS, Moscow

  26. Schematic rate of methylation376 b.p. 5'-flankingregion of tyrosinehydroxylase gene (-292 - +84) of rat brain hypothalamus Control Ladasten State Zakusov Institute of Pharmacology RAMS, Moscow

  27. Effects of Ladasten on catecholamine synthesis State Zakusov Institute of Pharmacology RAMS, Moscow

  28. Ladasten inhibits GABA transporter gene expression LADASTEN target gene house-keeping gene

  29. Ladastendecrease the amount of IL-1 (CEREP, France) • hypersomnia • exhaustion • activationhypothalamus-hypophysis axis • increase catecholaminesrelease • suppress appetite • decrease physical activity resistance IL-1 • depression like symptoms • decreaseexploratory behavior State Zakusov Institute of Pharmacology RAMS, Moscow

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