Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer's Disease and Senile Dementia

E.F. Shevtsova^*, D.V. Vinogradova, M.E. Neganova, P.N. Shevtsov, B.V. Lednev, S.O. Bachurin

Institute of Physiologically Active Compounds of the Russian Academy of Sciences, 1 Severny proezd, Moscow region, Chernogolovka, 142432 Russia,^*e-mail: shevtsova@ipac.ac.ru

Key words: neurodegenerative diseases; mitochondria; calcium; mitochondrial permeability transition pore; Dimebon

DOI: 10.18097/BMCRM00058

The review and summarizes own and literature data about the role of mitochondria as the important target in the search for drugs for the treatment of neurodegenerative diseases. Aging is a major risk factor for sporadic forms of various neurodegenerative diseases, including Alzheimer's disease. One of the most argued and currently accepted theories is the Mitochondrial Free Radical Theory of Aging. Mitochondrial hypotheses of the development of sporadic forms of neurodegenerative diseases particularly Alzheimer's disease, are closely connected with it. Impairments of mitochondrial functions lead to a decrease in their ability to regulate calcium homeostasis in the cell and to a decrease in the threshold for the induction of mitochondrial permeability transition (MPT) pores. MPT inhibitors can be considered as a promising approach to the treatment of neurodegenerative diseases, since these drugs can not only exhibit the properties of neuroprotectors, but also can provide normalization of synaptic activity due to increased calcium capacity of mitochondria. The review presents data on the number of MPT inhibitors, including endogenous compounds melatonin and N-acetylserotonin, their bioisosteric analogue Dimebon and a number of other compounds. The use of mitochondria as a basis for the formation of screening strategy for the search for compounds for the treatment of neurodegenerative diseases is of particular interest - both as a test of their potential toxicity, and as a basis for the creation of metabolic stimulants and drugs with neuroprotective and cognitive-stimulating effect.

ACKNOWLEDGEMENTS

This work was done in frames of the IPAC Research Program Framework 0090-2017-0019.

REFERENCES

1. Qiu C., Kivipelto M., von Strauss E. (2009). Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin. Neurosci, 11(2), 111–128. DOI
2. Eckert A., Schmitt K., Götz J. (2011). Mitochondrial dysfunction - the beginning of the end in Alzheimer’s disease? Separate and synergistic modes of tau and amyloid-β toxicity. Alzheimers. Res. Ther., 3(2), 15. DOI
3. Swerdlow R.H., Burns J.M., Khan S.M. (2014). The Alzheimer’s Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives. Biochimica et biophysica acta, 1842(8), 1219-1231. DOI
4. Caspersen C., Wang N., Yao J., Sosunov A., Chen X., Lustbader J.W., Xu H.W., Stern D., McKhann G., Yan S. Du. (2005). Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J., 19(14), 2040–2041. DOI
5. Shevtzova E.F., Kireeva E.G., Bachurin S.O. (2001). Effect of beta-amyloid peptide fragment 25-35 on nonselective permeability of mitochondria. Bull Exp Biol Med., 132(6), 1173-1176. DOI
6. Kumar A., Bodhinathan K., Foster T.C. (2009). Susceptibility to Calcium Dysregulation during Brain Aging. Front. Aging Neurosci., 1, 2. DOI
7. Oh M.M., Oliveira F. a., Waters J., Disterhoft J.F. (2013). Altered Calcium Metabolism in Aging CA1 Hippocampal Pyramidal Neurons. J. Neurosci., 33(18), 7905–7911. DOI
8. Mattson M.P. (2007). Calcium and neurodegeneration. Aging Cell., 6(3), 337–350. DOI
9. Lopez J.R., Lyckman A., Oddo S., Laferla F.M., Querfurth H.W., Shtifman A. (2008). Increased intraneuronal resting [Ca2+] in adult Alzheimer’s disease mice. J. Neurochem., 105(1), 262–271. DOI 10.1111/j.1471-4159.2007.05135.x
10. Crompton M. (1999). The mitochondrial permeability transition pore and its role in cell death. Biochem. J., 341, 233–249. DOI
11. Peng T., Jou M. (2010). Oxidative stress caused by mitochondrial calcium overload., 1201,183–188. DOI 10.1111/j.1749-6632.2010.05634.x
12. Rapizzi E., Pinton P., Szabadkai G., Wieckowski M.R., Vandecasteele G., Baird G., Tuft R.A., Fogarty K.E., Rizzuto R. (2002). Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J. Cell Biol., 159(4), 613–624. DOI
13. Giacomello M., Drago I., Pizzo P., Pozzan T. (2007). Mitochondrial Ca2+ as a key regulator of cell life and death. Cell Death Differ., 14(7), 1267–1274. DOI
14. Velikanov, G.A. (2013). Endoplasmic reticulum: Membrane contact sites Cell Tiss. Biol., 7, 504-511. https://doi.org/10.1134/S1990519X13060138
15. Gingrich JR, Pelkey KA, Fam SR, Huang Y, Petralia RS, Wenthold RJ, Salter MW. (2004). Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2. Proc Natl Acad Sci., 101, 6237–6241. DOI
16. Shevtsova, E.P., Dubova, L.G., Kireeva, E.G., Bachurin, S.O. (2006). Mitochondria as the memantine target. European Neuropsychopharmacology, 16, 243-244. DOI
17. Korde A.S., Maragos W.F. Identification of an N-methyl-D-aspartate receptor in isolated nervous system mitochondria. (2012). J Biol Chem., 287(42), 35192-35200. DOI
18. Bernardi P. (2013). The mitochondrial permeability transition pore: a mystery solved? Front. Physiol. Frontiers, 4, 95. DOI
19. Weeber E.J., Levy M., Sampson M.J., Anflous K., Armstrong D.L., Brown S.E., Sweatt J.D., Craigen W.J. (2002). The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity. J Biol Chem., 277(21), 18891-18897. DOI
20. Skulachev V.P. (2012). Mitochondria-Targeted Antioxidants as Promising Drugs for Treatment of Age-Related Brain Diseases. J. Alzheimers Dis., 28 (2), 283-289. DOI
21. Pavlov E., Zakharian E., Bladen C., Diao C.T.M., Grimbly C., Reusch R.N., French R.J. (2005). A large, voltage-dependent channel, isolated from mitochondria by water-free chloroform extraction. Biophys. J., 88(4), 2614–2625. DOI 10.1529/biophysj.104.057281
22. Abramov A.Y., Fraley C., Diao C.T., Winkfein R., Colicos M.A., Duchen M.R., French R.J., Pavlov E. (2007). Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death. Proc. Natl. Acad. Sci., 104(46), 18091–18096. DOI
23. Kokoszka J.E., Waymire K.G., Levy S.E., Sligh J.E., Cai J., Jones D.P., MacGregor G.R., Wallace D.C. (2004). The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature, 427(6973), 461–465. DOI
24. Varanyuwatana P., Halestrap A.P. (2012). The roles of phosphate and the phosphate carrier in the mitochondrial permeability transition pore. Mitochondrion, 12, 120–125. DOI
25. Papadopoulos V., Baraldi M., Guilarte T.R., Knudsen T.B., Lacapère J.-J., Lindemann P., Norenberg M.D., Nutt D., Weizman A., Zhang M.-R., Gavish M. (2006). Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol. Sci., 27(8), 402–409. DOI
26. Roestenberg P., Manjeri G.R., Valsecchi F., Smeitink J. a M., Willems P.H.G.M., Koopman W.J.H. (2012). Pharmacological targeting of mitochondrial complex I deficiency: the cellular level and beyond. // Mitochondrion, 12(1), 57–65. DOI
27. Giorgio V., von Stockum S., Antoniel M., Fabbro A., Fogolari F., Forte M., Glick G.D., Petronilli V., Zoratti M., Szabó I., Lippe G., Bernardi P. (2013). ATP synthase dimers form the mitochondrial PTP. PNAS, 110(15), 5887-5892. DOI
28. Bonora M., Bononi A., De Marchi E., Giorgi C., Lebiedzinska M., Marchi S., Patergnani S., Rimessi A., Suski J.M., Wojtala A., Wieckowski M.R., Kroemer G., Galluzzi L., Pinton P. (2013). Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle, 12(4), 674–683. DOI
29. He J., Ford H.C., Carroll J., Ding S., Fearnley I.M., Walker J.E. (2017). Persistence of the mitochondrial permeability transition in the. absence of subunit c of human ATP synthase. Proc Natl Acad Sci U S A, 114, 3409-3414. DOI
30. Kowaltowski A.J., Castilho R.F., Vercesi A.E. (2001). Mitochondrial permeability transition and oxidative stress. FEBS Lett., 495(1-2), 12–15. DOI
31. Luciano M., Patrizia S., Annarita A. (2011). Cyclosporine A in Ullrich Congenital Muscular Dystrophy: Long-Term Results. Oxidative Medicine and Cellular Longevity, 2011, 1-10. DOI
32. Nighoghossian N., Berthezène Y., Mechtouff L., Derex L., Cho TH., Ritzenthaler T., Rheims S., Chauveau F., Béjot Y., Jacquin A., Giroud M., Ricolfi F., Philippeau F., Lamy C., Turc G., Bodiguel E., Domigo V., Guiraud V., Mas J.L., Oppenheim C., Amarenco P., Cakmak S., Sevin-Allouet M., Guillon B., Desal H., Hosseini H., Sibon I., Mahagne M.H., Ong E., Mewton N., Ovize M. (2015). Cyclosporine in acute ischemic stroke. Neurology., 84(22), 2216-23. DOI
33. Atkinson K., Britton K., Biggs J. (1984). Distribution and concentration of cyclosporin in human blood. Journal of Clinical Pathology., 37(10), 1167-1171. DOI
34. Readnower R.D., Pandya J.D., McEwen M.L., Pauly J.R., Springer J.E., Sullivan P.G. (2011). Post-injury administration of the mitochondrial permeability transition pore inhibitor, NIM811, is neuroprotective and improves cognition after traumatic brain injury in rats. J. Neurotrauma, 28(9), 1845–1853. DOI
35. Korde A. S., Pettigrew L. C., Craddock S. D., Pocernich C. B., Waldmeier P. C., Maragos W. F. (2007). Protective Effects of NIM811 in Transient Focal Cerebral Ischemia Suggest Involvement of the Mitochondrial Permeability Transition. J. Neurotrauma, 24, 895−908. DOI
36. Wissing E. R., Millay D. P., Vuagniaux G., Molkentin J. D. (2010). Debio-025 Is More Effective Than Prednisone in Reducing Muscular Pathology in Mdx Mice. Neuromuscul. Disord., 20, 753−760. DOI
37. Warne J., Pryce G., Hill J.M., Shi X., Lennerås F., Puentes F., Kip M., Hilditch L., Walker P., Simone M.I., Chan A.W., Towers G.J., Coker A.R., Duchen M.R., Szabadkai G., Baker D., Selwood D.L. (2016). Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis. J Biol Chem., 291(9), 4356-4373. DOI
38. Roy S., Šileikytė J., Schiavone M., Neuenswander B., Argenton F., Aubé J., Hedrick M.P., Chung T.D., Forte M.A., Bernardi P., Schoenen F.J. (2015). Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem., 10(10), 1655-71. DOI
39. Averina E.B., Gracheva Y.A., Grishin Y.K., Radchenko E.V., Burmistrov V.V., Butov G.M., Neganova M.E., Serkova T.P., Redkozubova O.M., Shevtsova E.F., Milaeva E.R., Kuznetsova T.S., Zefirov N.S. (2016). Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole derivatives as lipoxygenase inhibitors and metabolism enhancing agents. Bioorganic & Medicinal Chemistry, 24(4), 712-720. DOI
40. Smith R.A., Adlam V.J., Blaikie F.H., Manas A.R., Porteous C.M., James A.M., Ross M.F., Logan A., Cochemé H.M., Trnka J., Prime T.A., Abakumova I., Jones B.A., Filipovska A., Murphy M.P. (2008). Mitochondria-targeted antioxidants in the treatment of disease. Ann N Y Acad Sci., 1147, 105-111. DOI
41. Rocha M., Hernandez-Mijares A., Garcia-Malpartida K., Bañuls C., Bellod L., Victor V.M. (2010). Mitochondria-targeted antioxidant peptides. Curr Pharm Des., 16(28), 3124-3131. DOI
42. Srinivasan V., Spence D.W., Pandi-Perumal S.R., Brown G.M., Cardinali D.P. (2011). Melatonin in Mitochondrial Dysfunction and Related Disorders. International Journal of Alzheimer’s Disease, 2011, 1-16. DOI
43. He H., Dong W., Huang F. (2010). Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer disease. Curr Neuropharmacol., 8(3), 211-217. DOI
44. Pandi-Perumal S.R., BaHammam A.S., Brown G.M., Spence D.W., Bharti V.K., Kaur C., Hardeland R., Cardinali D.P. (2013). Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res., 23(3), 267-300. DOI
45. Andrabi S.A., Sayeed I., Siemen D., Wolf G., Horn T.F. (2004). Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J., 18(7), 869-871. DOI
46. Bachurin S., Oxenkrug G., Lermontova N., Afanasiev A., Beznosko B., Vankin G., Shevtsova E., Mukhina T., Serkova T. (2000). N-Acetyl-Serotonin, Melatonin and Their Derivatives Improve Cognition and Protect Against beta-Amyloid-induced Neurotoxicity. Annals of NY Aca of Sci., 890, 156-166. DOI
47. Zhou H., Wang J., Jiang J., Stavrovskaya I.G., Li M., Li W., Wu Q., Zhang X., Luo C., Zhou S., Sirianni A.C., Sarkar S., Kristal B.S., Friedlander R.M., Wang X. (2014). N-acetyl-serotonin offers neuroprotection through inhibiting mitochondrial death pathways and autophagic activation in experimental models of ischemic injury. J Neurosci., 34(8), 2967-2978. DOI
48. Wang X., Figueroa B.E., Stavrovskaya I.G., Zhang Y., Sirianni A.C., Zhu S., Day A.L., Kristal B.S., Friedlander R.M. (2009). Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke, 40(5), 1877-85. DOI
49. Bachurin S.O., Shevtsova E.P., Kireeva E.G., Oxenkrug G.F., Sablin S.O. (2003). Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci., 993, 334-344. DOI
50. Millán-Plano Sergio, Eduardo Piedrafita, Francisco J. Miana-Mena , Lorena Fuentes-Broto. (2010). Melatonin and Structurally-Related Compounds Protect Synaptosomal Membranes from Free Radical Damage. J. Mol. Sci., 11, 312-328. DOI
51. Neganova M.E., Klochkov S.G., Afanasieva S.V., Chudinova E.S., Serkova T.P., Shevtsova E.F. (2014). Allomargaritarine as a basis for the creation of mitochondrial targeted potential neuroprotectors. Eur Neuropsychopharmacol., 24, 262. DOI
52. Lin X., Jun-Tian Z. (2004). Neuroprotection by D-securinine against neurotoxicity induced by beta-amyloid (25-35). Neurol Res., 26(7), 792-796. DOI
53. Raj D., Luczkiewicz M. (2008). Securinega suffruticosa. Fitoterapia, 79(6), 419-427. DOI
54. Neganova M.E., Serkova T.P., Klochkov S.G., Afanasieva S.V., Shevtsova E.F., Bachurin S.O. (2011). Neuroprotective properties of Allomargaritarine, a Novel Tryptamine Derivative of the Natural Alkaloid Securinine Natural and Technical Sciences., 5, 86-90.
55. Neganova M.E., Klochkov S.G., Afanasieva S.V., Serkova T.P., Chudinova E.S., Bachurin S.O., Reddy V.P., Aliev G., Shevtsova E.F. (2016). Neuroprotective effects of the securinine-analogues: identification of Allomargaritarine as a lead compound CNS & Neurological Disorders - Drug Targets, 15, 102-107. DOI : 10.2174/1871527314666150821111812
56. Neganova M.E., Klochkov S.G., Petrova L.N., Shevtsova E.F., Afanasieva S.V., Chudinova E..S, Fisenko V.P., Bachurin S.O., Barreto G.E., Aliev G. (2017). Securinine Derivatives as Potential Anti-amyloid Therapeutic Approach. CNS Neurol Disord Drug Targets, 16(3), 351-355. DOI
57. Neganova M.E., Blik V.A., Klochkov S.G., Chepurnova N.E., Shevtsova E.F. (2011). Investigation of the Antioxidant Characteristics of a New Tryptamine Derivative of Securinine and its Influence on Seizure Activity in the Brain in Experimental Epilepsy. Neurochemical Journal, 5, 208. DOI
58. Kim do Y., Simeone K.A., Simeone T.A., Pandya J.D., Wilke J.C., Ahn Y., Geddes J.W., Sullivan P.G., Rho J.M. (2015). Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann Neurol., 78(1), 77-87. DOI
59. Kudin A.P., Debska-Vielhaber G., Vielhaber S., Elger C.E., Kunz W.S. (2004). The mechanism of neuroprotection by topiramate in an animal model of epilepsy. Epilepsia, 45(12), 1478-1487. DOI
60. Matveeva I.A. (1983). Action of dimebon on histamine receptors. Pharmakology and Toxicology, 46(4), 27–29. DOI
61. Bachurin S.O., Shevtsova E.P., Kireeva E.G., Oxenkrug G.F., Sablin S.O. (2003). Mitochondria as a Target for Neurotoxins and Neuroprotective Agents. Ann. N.Y. Acad. Sci., 993, 334–344. DOI
62. Shevtsova E.F., Vinogradova D.V., Kireeva E.G., V. Prakash Reddy, Aliev G., Bachurin S.O. (2015). Dimebon Attenuates the Rat-Brain Mitochondrial Permeabilization. Current Alzheimer Research, 11(5), 422-429. DOI
63. Zhang S., Hedskog L., Petersen C.A., Winblad B., Ankarcrona M. (2010). Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J Alzheimers Dis., 21(2), 389-402. DOI
64. Bharadwaj P.R, Verdile G., Barr R.K., Gupta V., Steele J.W., Lachenmayer M.L., Yue Z., Ehrlich M.E., Petsko G., Ju S., Ringe D., Sankovich S.E., Caine J.M., Macreadie I.G., Gandy S., Martins R.N. (2012). Latrepirdine (dimebon) enhances autophagy and reduces intracellular GFP-Aβ42 levels in yeast. J Alzheimers Dis., 32(4), 949-67. DOI
65. Eckert S.H., Eckmann J., Renner K., Eckert G..P, Leuner K., Muller W.E. (2012). Dimebon ameliorates amyloid-β induced impairments of mitochondrial form and function. J Alzheimers Dis., 31(1), 21-32. DOI
66. Eckert S., Gaca J., Kolesova N. (2018). Mitochondrial Pharmacology of Dimebon (Latrepirdine) Calls for a New Look at its Possible Therapeutic Potential in Alzheimer’s Disease J. Aging Dis., 9(4), 729-744. DOI
67. Bachurin, V. Grigoriev, E. Shevtsova, I. Koroleva, L. Dubova, E. Kireeva. (2007). Anti-aging properties of Dimebon: Relation to mitochondrial permeability inhibition, Experimental Gerontology, 42(1–2), 142-143. DOI
68. Peters O.M., Shelkovnikova T., Tarasova T., Springe S., Kukharsky M.S., Smith G.A., Brooks S., Kozin S.A., Kotelevtsev Y., Bachurin S.O., Ninkina N., Buchman V.L. (2013). Chronic administration of Dimebon does not ameliorate amyloid-β pathology in 5xFAD transgenic mice. J Alzheimers Dis., 36(3), 589-596. DOI
69. Peters O.M, Connor-Robson N., Sokolov V.B., Aksinenko A.Y., Kukharsky M.S., Bachurin S.O., Ninkina N., Buchman V.L. (2013). Chronic administration of dimebon ameliorates pathology in TauP301S transgenic mice. J Alzheimers Dis., 33(4), 1041-1049. DOI
70. Bachurin S.O., Shelkovnikova T.A., Ustyugov A.A., Peters O., Khritankova I., Afanasieva M.A., Tarasova T.V., Alentov I.I., Buchman V.L., Ninkina N.N. (2012). Dimebon slows progression of proteinopathy in γ-synuclein transgenic mice. Neurotox Res., 22(1), 33-42. DOI
71. Ustyugov A.A., Shelkovnikova T.A., Kokhan V.S., Khritankova I..V, Peters O., Buchman V.L., Bachurin S.O., Ninkina N.N. (2012). Dimebon reduces the levels of aggregated amyloidogenic protein forms in detergent-insoluble fractions in vivo. Bull Exp Biol Med., 152(6), 731-733. DOI
72. Yamashita M., Nonaka T., Arai T., Kametani F., Buchman V.L., Ninkina N., Bachurin S.O., Akiyama H., Goedert M., Hasegawa M. (2009). Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Lett., 583(14), 2419-2424. DOI
73. Khritankova I.V., Kukharskiy M.S., Lytkina O.A., Bachurin S.O., Shorning B.Y. (2012). Dimebon activates autophagosome components in human neuroblastoma SH-SY5Y cells. Dokl Biochem Biophys., 446, 251-253. DOI
74. Pieper A.A, Xie S., Capota E., Estill S.J., Zhong J., Long J.M., Becker G.L., Huntington P., Goldman S.E., Shen C.H., Capota M., Britt J.K., Kotti T., Ure K., Brat D.J., Williams N.S., MacMillan K.S., Naidoo J., Melito L., Hsieh J., De Brabander J., Ready J.M., McKnight S.L. (2010). Discovery of a proneurogenic, neuroprotective chemical. Cell, 142(1), 39-51. DOI
75. Hou Y., Mattson M.P., Cheng A. (2013). Permeability Transition Pore-Mediated Mitochondrial Superoxide Flashes Regulate Cortical Neural Progenitor Differentiation. PLoS ONE, 8(10), 76721. DOI
76. Shin J.Y., Kong S.Y., Yoon H.J., Ann J., Lee J., Kim H.J. (2015). An Aminopropyl Carbazole Derivative Induces Neurogenesis by Increasing Final Cell Division in Neural Stem Cells. Biomol Ther (Seoul), 23(4), 313-319. DOI
77. Wang G., Han T., Nijhawan D., Theodoropoulos P., Naidoo J., Yadavalli S., Mirzaei H., Pieper A.A., Ready J.M., McKnight S.L. (2014). P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell, 158(6), 1324-1334. DOI
78. Wang S.N., Xu T.Y., Wang X., Guan Y.F., Zhang S.L., Wang P., Miao C.Y. (2016). Neuroprotective Efficacy of an Aminopropyl Carbazole Derivative P7C3-A20 in Ischemic Stroke. CNS Neurosci Ther, 22(9), 782-788. DOI
79. Jiang B., Song L., Huang C., Zhang W. (2016). P7C3 Attenuates the Scopolamine-Induced Memory Impairments in C57BL/6J Mice. Neurochem Res., 41(5), 1010-1019. DOI
80. Blaya M.O., Bramlett H.M., Naidoo J., Pieper A.A., Dietrich W.D. (2014). Neuroprotective efficacy of a proneurogenic compound after traumatic brain injury. J Neurotrauma, 31(5), 476-486. DOI
81. Kuharskiy M.S., Ovchinnikov R.K., Ustyugov A.A., Bachurin S.O. (2014). Molecular Aspects of Pathogenesis and Modern Appoaches to Pharmacological Correction of Alzheimer's Disease. Neurodegenerative Diseases: from the Genome to the Whole Organism, Ed. M.V.Ugryumov, Moscow, Scientific World, 2, 137-162.
82. Bachurin S. (2015). Contemporary Approaches for Pharmacological Intervention of Abundant Neurodegenerative Disorders. J Nanomedine Biotherapeutic Discov, 5(2), 137. DOI