Small molecules activating TrkB receptor for treating a variety of CNS disorders

CNS and Neurological Disorders - Drug Targets

Volumn 12, Issue 7, 2013, Pages 1066-1077

  Zeng, Yan ^a   Wang, Xiaonan ^a   Wang, Qiang ^a   Liu, Shumin ^a   Hu, Xiamin ^a   Mcclintock, Shawn M ^b,c  

^a WUHAN UNIVERSITY OF SCIENCE AND TECHNOLOGY   (China)

^b DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

Alzheimer's disease; Brain derived neurotrophic factor; Cns disorders; Depression; Learning and memory; Mimetics; Small molecule; Synaptic plasticity; Tropomyosin receptor kinase b

Indexed keywords

2 [4 (2 CARBOXYETHYL) PHENETHYLAMINO] ADENOSINE 5' (N ETHYLCARBOXAMIDE); 2 [4 (2 CARBOXYETHYL)PHENETHYLAMINO]ADENOSINE 5' (N ETHYLCARBOXAMIDE); 4' DIMETHYLAMINO 7, 8 DIHYDROXYFLAVONE; 7, 8 DIHYDROXYFLAVONE; ADENOSINE; ADENOSINE A2A RECEPTOR AGONIST; BRAIN DERIVED NEUROTROPHIC FACTOR; BRAIN DERIVED NEUROTROPHIC FACTOR RECEPTOR; CENTRAL NERVOUS SYSTEM AGENTS; DEOXYGEDUNIN; LM22A 4; MITOGEN ACTIVATED PROTEIN KINASE; NEUROTROPHIN; PHOSPHATIDYLINOSITOL 3 KINASE; REACTIVE OXYGEN METABOLITE; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; BINDING AFFINITY; CENTRAL NERVOUS SYSTEM DISEASE; CEREBROVASCULAR ACCIDENT; DEPRESSION; DRUG POTENCY; GENETIC POLYMORPHISM; HUNTINGTON CHOREA; LONG TERM POTENTIATION; MEMORY DISORDER; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; SURVIVAL; TRANSACTIVATION;

ADENOSINE A2 RECEPTOR AGONISTS; ANIMALS; CENTRAL NERVOUS SYSTEM DISEASES; FLAVONES; HUMANS; MOLECULAR TARGETED THERAPY; PEPTIDOMIMETICS; RECEPTOR, TRKB; SIGNAL TRANSDUCTION;

EID: 84889047627     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/18715273113129990089     Document Type: Article

References (116)

1. Lessmann, V.; Gottmann, K.; Malcangio, M. Neurotrophin secretion: current facts and future prospects. Prog. Neurobiol., 2003, 69(5), 341-374. Zeng et al.
2. Chao, M.V. Neurotrophins and Their Receptors: a Convergence point for many Signaling pathways. Nat. Rev. Neurosci., 2003, 4(4), 299-309.
3. Tonchev, A.B.; Yamashima, T. Transcribing postischemic neurogenesis: a tale revealing hopes of adult brain repair. J. Mol. Med. (Berl.), 2007, 85(6), 539-542.
4. Hsu, Y.C.; Lee, D.C.; Chiu, I.M. Neural stem cells, neural progenitors, and neurotrophic factors. Cell Transplant., 2007, 16(2), 133-150.
5. Huang, E.J.; Reichardt, L.F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem., 2003, 72, 609-642.
6. Teng, K.K.; Hempstead, B.L. Neurotrophins and their receptors: signaling trios in complex biological systems. Cell Mol. Life Sci., 2004, 61(1), 35-48.
7. Kaplan, D.R.; Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol., 2000, 10(3), 381-391.
8. Chao, M.V.; Bothwell, M. Neurotrophins: to cleave or not to cleave. Neuron, 2002, 33(1), 9-12.
9. Allen, S.J., Dawbarn, D. Clinical relevance of the neurotrophins and their receptors. Clin. Sci. (Lond.), 2006, 110(2), 175-191.
10. Duman, R.S.; Monteggia, L.M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry, 2006, 59(12), 1116-1127.
11. Zuccato, C.; Cattaneo, E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol., 2009, 5(6), 311-322.
12. Angelucci, F.; Spalletta, G.; diIulio, F.; Ciaramella, A.; Salani, F.; Colantoni, L.; Varsi, A.E.; Gianni, W.; Sancesario, G.; Caltagirone, C.; Bossù, P. Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients are characterized by increased BDNF serum levels. Curr. Alzheimer Res., 2010, 7(1), 15-20.
13. O'Bryant, S. E.; Hobson, V. L.; Hall, J. R.; Barber, R. C.; Zhang, S.; Johnson, L.; Diaz-Arrastia, R. Serum brain-derived neurotrophic factor levels are specifically associated with memory performance among Alzheimer's disease cases. Dement. Geriatr. Cogn. Disord., 2011, 31(1), 31-36.
14. Balu, D.T.; Coyle, J.T. Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci. Biobehav. Rev., 2011, 35(3), 848-870.
15. Blugeot, A.; Rivat, C.; Bouvier, E.; Molet, J.; Mouchard, A.; Zeau, B.; Bernard, C.; Benoliel, J. J.; Becker, C. Vulnerability to depression: from brain neuroplasticity to identification of biomarkers. J. Neurosci., 2011, 31(36), 12889-12899.
16. Karege, F.; Perret, G.; Bondolfi, G.; Schwald, M.; Bertschy, G.; Aubry, J.M. Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res., 2002, 109(2), 143-148.
17. Zeng, Y.; Tan, M.; Kohyama, J.; Sneddon, M.; Watson, J. B.; Sun, Y. E.; Xie, C. W. Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging. J. Neurosci., 2011, 31(49), 17800-17810.
18. Zeng, Y.; Liu, Y.; Wu, M.; Liu, J.; Hu, Q. Activation of TrkB by 7, 8-dihydroxyflavone prevents fear memory defects and facilitates amygdalar synaptic plasticity in aging. J. Alzheimers. Dis., 2012, 31(4), 765-778.
19. Zeng, Y.; Lv, F.; Li, L.; Yu, H.; Dong, M.; Fu, Q. 7, 8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats. J. Neurochem., 2012, 122(4), 800-811.
20. Tapia-Arancibia, L.; Aliaga, E.; Silhol, M.; Arancibia, S. New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res. Rev., 2008, 59(1), 201-220.
21. Longo, F. M.; Yang, T.; Knowles, K.J.; Xie, Y.; Moore, A. L.; Massa, M. S., Small molecule neurotrophin receptor ligands: novel strategies for targeting Alzheimer's disease mechanisms. Curr. Alzheimer. Res., 2007, 4 (5), 503-506.
22. Nagahara, A.H.; Merrill, D.A.; Coppola, G.; Tsukada, S.; Schroeder, B. E.; Shaked, G. M.; Wang, L.; Blesch, A.; Kim, A.; Conner, J. M.; Rockenstein, E.; Chao, M. V.; Koo, E. H.; Geschwind, D.; Masliah, E.; Chiba, A. A.; Tuszynski, M. H. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat. Med., 2009, 15(3), 331-337.
23. Schulte-Herbrüggen, O.; Braun, A.; Rochlitzer, S.; Jockers-Scherübl, M.C.; Hellweg, R. Neurotrophic factors--a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases? Curr. Med. Chem., 2007, 14(22), 2318-2329. Small Molecules Activating TrkB Treating CNS Disorders
24. Wollen, K.A. Alzheimer's disease: the pros and cons of pharmaceutical, nutritional, botanical, and stimulatory therapies, with a discussion of treatment strategies from the perspective of patients and practitioners. Altern. Med. Rev., 2010, 15(3), 223-244.
25. O'Leary, P.D.; Hughes, R.A. Design of potent peptide mimetics of brain-derived neurotrophic factor.J. Biol. Chem., 2003, 278(28), 25738-25744.
26. Williams, G.; Williams, E.J.; Maison, P.; Pangalos, M.N.; Walsh, F.S.; Doherty, P. Overcoming the inhibitors of myelin with a novel neurotrophin strategy.J. Biol. Chem., 2005, 280(7), 5862-5869.
27. Fletcher, J. M.; Hughes, R., A. Novel monocyclic and bicyclic loop mimetics of brain-derived neurotrophic factor. J. Pept. Sci., 2006, 12(8), 515-524.
28. Fletcher, J. M.; Hughes, R. A., Modified low molecular weight cyclic peptides as mimetics of BDNF with improved potency, proteolytic stability and transmembrane passage in vitro. Bioorg. Med. Chem., 2009, 17(7), 2695-2702.
29. Molina-Holgado, F.; Doherty, P.; Williams, G. Tandem repeat peptide strategy for the design of neurotrophic factor mimetics. CNS. Neurol. Disord. Drug Targets, 2008, 7(1), 110-119.
30. Massa, S.M.; Yang, T.; Xie, Y.; Shi, J.; Bilgen, M.; Joyce, J.N.; Nehama, D.; Rajadas, J.; Longo, F.M. Small molecule BDNF-mimetics activate TrkB signalin and prevent neuronal degeneration in rodents.J. Clin. Invest, 2010, 120(5), 1774-1785.
31. Jang, S.W.; Liu, X.; Yepes, M.; Shepherd, K.R.; Miller, G.W.; Liu, Y.; Wilson, W.D.; Xiao, G.; Blanchi, B.; Sun, Y.E.; Ye, K. A selective TrkB agonist with potent neurotrophic activities by 7, 8-dihydroxyflavone. Proc. Natl. Acad. Sci.USA, 2010, 107(6), 2687-2692.
32. Liu, X.; Chan, C. B.; Qi, Q.; Xiao, G.; Luo, H. R.; He, X.; Ye, K. Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7, 8-dihydroxyflavone active in mouse models of depression. J. Med. Chem., 2012, 55(19), 8524-8537.
33. Harborne, J.B.; Williams, C.A. Advances in flavonoid research since 1992. Phytochemistry, 2000, 55(6), 481-504.
34. Galli, R.L.; Shukitt-Hale, B.; Youdim, K.A.; Joseph, J.A. Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits. Ann. NY Acad. Sci., 2002, 959, 128-132.
35. Haque, A.M.; Hashimoto, M.; Katakura, M.; Tanabe, Y.; Hara, Y.; Shido, O. Long-term administration of green tea catechins improves spatial cognition learning ability in rats.J. Nutr., 2006, 136(4), 1043-1047.
36. Youdim, K.A.; Spencer, J.P.; Schroeter, H.; Rice-Evans, C. Dietary flavonoids as potential neuroprotectants. Biol Chem., 2002, 383(3-4), 503-519.
37. Youdim, K.A.; Joseph, J.A. A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: a multiplicity of effects. Free Radic. Biol. Med., 2001, 30(6), 583-594.
38. Kuriyama, S.; Hozawa, A.; Ohmori, K.; Shimazu, T.; Matsui, T.; Ebihara, S.; Awata, S.; Nagatomi, R.; Arai, H.; Tsuji, I. Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am.J. Clin. Nutr., 2006, 83(2), 355-361.
39. Wang, Y.; Wang, L.; Wu, J.; Cai, J. The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats. Br.J. Pharmacol., 2006, 148(2), 147-153.
40. Spencer, P.E.J. The interactions of flavonoids within neuronal signalling pathways. Genes Nutr., 2007, 2(3), 257-273.
41. Spencer, P.E.J. Flavonoids and brain health: multiple effects underpinned by common mechanisms. Genes Nutr., 2009, 4(4), 243-250.
42. Liu, X.; Chan, C. B.; Jang, S. W.; Pradoldej, S.; Huang, J.; He, K.; Phun, L.H.; France, S.; Xiao, G.; Jia, Y.; Luo, H. R.; Ye, K. A Synthetic 7, 8-Dihydroxyflavone Derivative Promotes Neurogenesis and Exhibits Potent Antidepressant Effect. J. Med. Chem., 2010, [Epub ahead of print].
43. Choi, D.C.; Maguschak, K.A.; Ye, K.; Jang, S.W.; Myers, K.M.; Ressler, K.J. Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear. Proc. Natl. Acad. Sci. USA, 2010, 107(6), 2675-2680.
44. Lee, J.; Duan, W.; Mattson, M. P. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J. Neurochem., 2002, 82(6), 1367-1375.
45. Kaplan, D.R.; Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol., 2000, 10(3), 381-391.
46. Pang, P.T.; Teng, H.K.; Zaitsev, E.; Woo, N.T.; Sakata, K.; Zhen, S.; Teng, K.K.; Yung, W.H.; Hempstead, B.L.; Lu, B. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science, 2004, 306(5695), 487-491.
47. Medina, L.D.; Sciarretta, C.; Calella, M.A.; Halbach, B.O.; Unsicker, K.; Minichiello, L. TrkB regulates neocortex formation through the Shc/PLCc-mediated control of neuronal migration. The EMBO. Journal, 2004, 23(19), 3803-3814.
48. Devi, L.; Ohno, M. 7, 8-dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer's disease. Neuropsychopharmacology, 2012, 37(2), 434-444.
49. Andero, R.; Heldt, S.A.; Ye, K.; Liu, X.; Armario, A.; Ressler, K.J. Effect of 7, 8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning. Am.J. Psychiatry. 2011, 168(2), 163-172.
50. Andero, R.; Daviu, N.; Escorihuela, R. M.; Nadal, R.; Armario, A. 7, 8-dihydroxyflavone, a Trk B receptor agonist, blocks long-term spatial memory impairment caused by immobilization stress in rats. Hippocampus, 2012, 22(3), 399-408.
51. Chen, J.; Chua, K.W.; Chua, C.C.; Yu, H.; Pei, A.; Chua, B.H.; Hamdy, R.C.; Xu, X.; Liu, C.F. Antioxidant activity of 7, 8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity. Neurosci. Lett., 2011, 499(3), 181-185.
52. Gupta, V.K.; You, Y.; Li, J.C.; Klistorner, A.; Graham, S. L. Protective effects of 7, 8-dihydroxyflavone on retinal ganglion and RGC-5 cells against excitotoxic and oxidative stress. J. Mol. Neurosci., 2013, 49(1), 96-104.
53. Park, H.Y.; Kim, G.Y.; Hyun, J.W.; Hwang, H.J.; Kim, N.D.; Kim, B.W.; Choi, Y.H. 7, 8-Dihydroxyflavone exhibits anti-inflammatory properties by downregulating the NF-B and MAPK signaling pathways in lipopolysaccharide-treated RAW264.7 cells. Int.J. Mol. Med., 2012, 29(6), 1146-1152.
54. Park, H. Y.; Kim, G. Y.; Kwon, T. K.; Hwang, H. J.; Kim, N. D.; Yoo, Y. H.; Choi, Y. H. Apoptosis induction of human leukemia U937 cells by 7, 8-dihydroxyflavone hydrate through modulation of the Bcl-2 family of proteins and the MAPKs signaling pathway. Mutat. Res., 2013, 751(2), 101-108.
55. Tsai, T.; Klausmeyer, A.; Conrad, R.; Gottschling, C.; Leo, M.; Faissner, A.; Wiese, S. 7, 8-Dihydroxyflavone leads to survival of cultured embryonic motoneurons by activating intracellular signaling pathways. Mol. Cell Neurosci., 2013, 56C, 18-28.
56. Boulanger, L.M.; Poo, M.M. Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation. Nat. Neurosci., 1999, 2(4), 346-351.
57. Marongiu, D.; Imbrosci, B.; Mittmann, T. Modulatory effects of the novel TrkB receptor agonist 7, 8-dihydroxyflavone on synaptic transmission and intrinsic neuronal excitability in mouse visual cortex in vitro. Euo.J. Pharmacol., 2013, S0014-2999(13), 00262-00268.
58. Jarrard, L.E. On the role of the hippocampus in learning and memory in the rat. Behav. Neural. Biol., 1993, 60(1), 9-26.
59. Yamada, K.; Nabeshima, T., J. Brain-derived neurotrophic factor/TrkB signaling in memory processes. Pharmacol. Sci., 2003, 91(4), 267-270.
60. Dwivedi, Y. Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr. Dis. Treat, 2009, 5, 433-449.
61. Krishnan, V.; Nestler, E. J. Linking molecules to mood: new insight into the biology of depression. Am.J. Psychiatry, 2010, 167(11), 1305-1320.
62. Kimpton, J. The brain derived neurotrophic factor and influences of stress in depression. Psychiatr. Danub., 2012, 167(11), S169-171.
63. Numata, S.; Ueno, S.; Iga, J.; Yamauchi, K.; Hongwei, S.; Ohta, K.; Kinouchi, S.; Shibuya-Tayoshi, S.; Tayoshi, S.; Aono, M.; Kameoka, N.; Sumitani, S.; Tomotake, M.; Kaneda, Y.; Taniguchi, T.; Ishimoto, Y.; Ohmori, T. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms. Neurosci. Lett., 2006, 401(1-2), 1-5.
64. Frielingsdorf, H.; Bath, K.G.; Soliman, F.; Difede, J.; Casey, B.J.; Lee, F.S. Variant brain-derived neurotrophic factor Val66Met endophenotypes: implications for posttraumatic stress disorder. Ann. NY Acad. Sci., 2010, 1208, 150-157.
65. Rybakowski, J.K. BDNF gene: functional Val66Met polymorphism in mood disorders and schizophrenia. Pharmacogenomics, 2008, 9(11), 1589-1593.
66. Sun, M. M.; Yang, L. M.; Wang, Y.; Feng, X.; Cui, K. Y.; Liu, L. F.; Chen, Z. Y. BDNF Val66Met polymorphism and anxiety/depression symptoms in schizophrenia in a Chinese Han population. Psychiatr. Genet., 2013, 23(3), 124-129.
67. Lee, Y.; Lim, S. W.; Kim, S. Y.; Chung, J. W.; Kim, J.; Myung, W.; Song, J.; Kim, S.; Carroll, B.J.; Kim, D.K. Association between the BDNF Val66Met Polymorphism and Chronicity of Depression. Psychiatry Investig., 2013, 10(1): 56-61.
68. Baker-Andresen, D.; Flavell, C.R.; Li, X.; Bredy, T.W. Activation of BDNF signaling prevents the return of fear in female mice. Learn. Mem., 2013, 20(5), 237-240.
69. Choi, D.C.; Gourley, S.L.; Ressler, K.J. Prelimbic BDNF and TrkB signaling regulates consolidation of both appetitive and aversive emotional learning. Transl. Psychiatry, 2012, 18, 2, e205.
70. Blugeot, A.; Rivat, C.; Bouvier, E.; Molet, J.; Mouchard, A.; Zeau, B.; Bernard, C.; Benoliel, J.J.; Becker, C. Vulnerability to depression: from brain neuroplasticity to identification of biomarkers. J. Neurosci., 2011, 31(36), 12889-12899.
71. Andero, R.; Ressler, K.J. Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes Brain Behav., 2012, 11(5), 503-512.
72. Tzeng, W.Y.; Chuang, J.Y.; Lin, L.C.; Cherng, C.G.; Lin, K.Y.; Chen, L.H.; Su, C.C.; Yu, L. Companions reverse stressor-induced decreases in neurogenesis and cocaine conditioning possibly by restoring BDNF and NGF levels in dentate gyrus. Psychoneuroendocrinology, 2012, [Epub ahead of print].
73. Ren, Q.; Zhang, J. C.; Fujita, Y.; Ma, M.; Wu, J.; Hashimoto, K. Effects of TrkB agonist 7, 8-dihydroxyflavone on sensory gating deficits in mice after administration of methamphetamine. Pharmacol. Biochem. Behav., 2013, 106C, 124-127.
74. Liu, X.; Qi, Q.; Xiao, G.; Li, J.; Luo, H.R.; Ye, K. O-Methylated metabolite of 7, 8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity. Pharmacology, 2013, 91(3-4), 185-200.
75. Park, H.Y.; Kim, G.Y.; Kwon, T.K.; Hwang, H.J.; Kim, N.D.; Yoo, Y.H.; Choi, Y.H. Mutat. Res., 2012, doi:pii: S1383-5718(12)00358-0.
76. Zhang, R.; Kang, K. A.; Piao, M. J.; Ko, D. O.; Wang, Z. H.; Chang, W.Y.; You, H.; Lee, I.K.; Kim, B. J.; Kang, S.S.; Hyun, J. W. Preventive effect of 7, 8-dihydroxyflavone against oxidative stress induced genotoxicity. Biol. Pharm. Bull, 2009, 32(2), 166-171.
77. Jiang, M.; Peng, Q.; Liu, X.; Jin, J.; Hou, Z.; Zhang, J.; Mori, S.; Ross, C. A.; Ye, K.; Duan, W. Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington's disease. Hum. Mol. Genet., 2013, [Epub ahead of print]
78. Uluç, K.; Kendigelen, P.; Fidan, E.; Zhang, L.; Chanana, V.; Kintner, D.; Aktüre, E.; Song, C.; Ye, K.; Sun, D.; Ferrazzano, P.; Cengiz, P. TrkB Receptor Agonist 7, 8 Dihydroxyflavone Triggers Profound Gender-Dependent Neuroprotection in Mice after Perinatal Hypoxia and Ischemia. CNS Neurol. Disord. Drug Targets, 2013, [Epub ahead of print]
79. Kermani, P.; Hempstead, B. A Newly Described Mediator of Angiogenesis. Trends. Cardiovasc. Med., 2007, 17(4), 140-143.
80. Griffioen, A.W.; Molema, G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol. Rev., 2000, 52(2), 237-268.
81. Johnson, R.A.; Lam, M.; Punzo, A.M.; Li, H.; Lin, B.R.; Ye, K.; Mitchell, G.S.; Chang, Q. 7, 8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome. J. Appl. Physiol., 2012, 112(5), 704-710.
82. Mantilla, C.B.; Sieck, G.C. Phrenic motor unit recruitment during ventilatory and non-ventilatory behaviors.Respir Physiol Neurobiol. Respir. Physiol. Neurobiol., 2011, 179(1), 57-63.
83. Zhan, W.Z.; Mantilla, C.B.; Sieck, G.C. Regulation of neuromuscular transmission by neurotrophins. Sheng Li Xue Bao, 2003, 55(6), 617-624.
84. Mantilla, C.B.; Ermilov, L.G. The novel TrkB receptor agonist 7, 8-dihydroxyflavone enhances neuromuscular transmission. Muscle Nerve, 2012, 45(2), 274-276.
85. Chen, X.; Ye, H.; Kuruvilla, R.; Ramanan, N.; Scangos, K.W.; Zhang, C.; Johnson, N.M.; England, P.M.; Shokat, K.M.; Ginty, D.D. A chemical-genetic approach to studying neurotrophin signaling. Neuron, 2005, 46(1), 13-21.
86. Jang, S.W.; Liu, X.; Chan, C.B.; France, S. A.; Sayeed, I.; Tang, W.; Lin, X.; Xiao, G.; Andero, R.; Chang, Q.; Ressler, K.J.; Ye, K. Deoxygedunin, a natural product with potent neurotrophic activity in mice. PLoS. One, 2010, 5(7), 1-15.
87. Yu, Q.; Chang, Q.; Liu, X.; Gong, S.; Ye, K.; Lin, X. 7, 8, 3'-Trihydroxyflavone, a potent small molecule TrkB receptor agonist, protects spiral ganglion neurons from degeneration both in vitro and in vivo. Biochem. Biophys. Res. Commun., 2012, 422(3), 387-392.
88. Lewin, G.R.; Barde, Y.-A. Physiology of the neurotrophins. Annu. Rev. Neuroscience, 1996, 19, 289-317.
89. Fredholm, B.B.; Arslan, G.; Halldner, L.; Kull, B.; Schulte, G.; Wasserman, W., Naunyn. Structure and function of adenosine receptors and their genes. Schmiedebergs Arch. Pharmacol., 2000, 362(4-5), 364-374.
90. Lee, F.S.; Chao, M.V. Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc. Natl. Acad. Sci. USA., 2001, 98(6), 3555-3560.
91. Lee, F.S.; Rajagopal, R.; Kim, A.H.; Chang, P.C.; Chao, M.V. Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides. J. Biol. Chem., 2002, 277(11), 9096-9102.
92. Jeanneteau, F.; Chao, M.V. Promoting neurotrophic effects by GPCR ligands. Novartis Found Symp., 2006, 276, 181-189.
93. Rajagopal, R.; Chao, M.V. A role for Fyn in Trk receptor transactivation by G-protein-coupled receptor signaling. Mol. Cell Neurosci., 2006, 33(1), 36-46.
94. Jarvis, M.F.; Schulz, R.; Hutchison, A.J.; Do, U.H.; Sills, M.A.; Williams, M. [3H]CGS 21680, a selective A2 adenosine receptor agonist directly labels A2 receptors in rat brain.J. Pharmacol. Exp. Ther., 1989, 251(3), 888-893.
95. Canals, M.; Angulo, E.; Casadó, V.; Canela, E.I.; Mallol, J.; Viñals, F.; Staines, W.; Tinner, B.; Hillion, J.; Agnati, L.; Fuxe, K.; Ferré, S.; Lluis, C.; Franco, R. Molecular mechanisms involved in the adenosine A and A receptor-induced neuronal differentiation in neuroblastoma cells and striatal primary cultures. J. Neurochem., 2005, 92(2), 337-348.
96. Nagappan, G.; Woo, N.H.; Lu, B. Ama zinc link between TrkB transactivation and synaptic plasticity. Neuron, 2008, 57(4), 477-479.
97. Lee, F.S.; Rajagopal, R.; Chao, M.V. Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors. Cytokine Growth Factor Rev., 2002, 13(1), 11-17.
98. Rajagopal, R.; Chen, Z.Y.; Lee, F.S.; Chao, M.V. Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. J. Neurosci., 2004, 24(30), 6650-6658.
99. Berg, M.M.; Sternberg, D.W.; Parada, L.F.; Chao, M.V. K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity.J. Biol. Chem., 1992, 267(34), 13-16.
100. Diogenes, M.J.; Fernandes, C.C.; Sebastiao, A.M.; Ribeiro, J.A. Activation of adenosine A2A receptor facilitates brain-derived neurotrophic factor modulation of synaptic transmission in hippocampal slices. J. Neurosci., 2004, 24(12), 2905-2913.
101. Mojsilovic-Petrovic, J.; Jeong, G.B.; Crocker, A.; Arneja, A.; David, S.; Russell, D.S.; Kalb, R.G. Protecting motor neurons from toxic insult by antagonism of adenosine A2a and Trk receptors. J. Neurosci., 2006, 26(36), 9250-9263.
102. Wiese, S.; Jablonka, S.; Holtmann, B.; Orel, N.; Rajagopal, R.; Chao, M.V.; Sendtner, M. Adenosine receptor A2A-R contributes to motoneuron survival by transactivating the tyrosine kinase receptor TrkB. Proc. Natl. Acad. Sci. USA, 2007, 104(43), 17210-17215.
103. F.J. Receptor tyrosine kinases and respiratory motor plasticity. Respir. Physiol. Neurobiol., 2008, 164(1-2), 242-251.
104. Tebano, M.T.; Martire, A.; Potenza, R.L.; Gro, C.; Pepponi, R.; Armida, M.; Domenici, M.R.; Schwarzschild, M.A.; Chen, J.F.; Popoli, P. Adenosine A(2A) receptors are required for normal BDNF levels and BDNF-induced potentiation of synaptic transmission in the mouse hippocampus. J. Neurochem., 2008, 104(1), 279-286. Small Molecules Activating TrkB Treating CNS Disorders
105. Fontinha, B.M.; Diogenes, M.J.; Ribeiro, J.A.; Sebastiao, A.M. Enhancement of long-term potentiation by brain-derived neurotrophic factor requires adenosine A2A receptor activation by endogenous adenosine. Neuropharmacology, 2008, 54(6), 924-933.
106. Komaki, S.; Ishikawa, K.; Arakawa, Y. Trk and cAMP-dependent survival activity of adenosine A(2A) agonist CGS21680 on rat motoneurons in culture. Neurosci. Lett., 2012, 522(1), 21-24.
107. Chou, S.Y.; Lee, Y.C.; Chen, H.M.; Chiang, M.C.; Lai, H.L.; Chang, H.H.; Wu, Y.C.; Sun, C.N.; Chien, C.L.; Lin, Y.S.; Wang, S.C.; Tung, Y.Y.; Chang, C.; Chern, Y. CGS21680 attenuates symptoms of Huntington's disease in a transgenic mouse model. J. Neurochem., 2005, 93(2), 310-320.
108. Yanpallewar, S.U.; Barrick, C.A.; Buckley, H.; Becker, J.; Tessarollo, L. Deletion of the BDNF truncated receptor TrkB.T1 delays disease onset in a mouse model of amyotrophic lateral sclerosis. PLoS. One, 2012, 7(6), e39946.
109. Kaster, M.P.; Rosa, A.O.; Rosso, M.M.; Goulart, E.C.; Santos, A.R.; Rodrigues, A.L. Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors. Neurosci. Lett., 2004, 355(1-2), 21-24.
110. Domeniconi, M.; Chao, M.V. Transactivation of Trk receptors in spinal motor neurons. Histol. Histopathol., 2010, 25(9), 1207-1213.
111. Sebastião, A.M.; Assaife-Lopes, N.; Diógenes, M.J.; Vaz, S.H.; Ribeiro, J.A. Modulation of brain-derived neurotrophic factor (BDNF) actions in the nervous system by adenosine A(2A) receptors and the role of lipid rafts. Biochim. Biophys. Acta, 2011, 1808(5), 1340-1349.
112. Saragovi, H.U.; Gehring, K. Development of pharmacological agents for targeting neurotrophins and their receptors. Trends. Pharmacol. Sci., 2000, 21(3), 93-98.
113. Dagø, L.; Bonde, C.; Peters, D.; Møller, A.; Bomholt, S.F.; Hartz, J.B.; Meyer, M.; Drejer, J.; Grønborg, M. NS 1231, a novel compound with neu-rotrophic-like effects in vitro and in vivo. J. Neurochem., 2002, 81(1), 17-24.
114. Han, J.; Pollak, J.; Yang, T.; Siddiqui, M.R.; Doyle, K.P.; Taravosh-Lahn, K.; Cekanaviciute, E.; Han, A.; Goodman, J.Z.; Jones, B.; Jing, D.; Massa, S.M.; Longo, F.M.; Buckwalter, M.S. Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. Stroke, 2012, 43(7), 1918-1924.
115. Schmid, D.A.; Yang, T.; Ogier, M.; Adams, I.; Mirakhur, Y.; Wang, Q.; Massa, S.M.; Longo, F.M.; Katz, D.M. A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. J. Neurosci., 2012, 32(5), 1803-1810.
116. Price, R.D.; Milne, S.A.; Sharkey, J.; Matsuoka, N. Advances in small molecules promoting neurotrophic function. Pharmacol. Therapeutics, 2007, 115(2), 292-306.