Biology:Neurotrophin mimetics

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Short description: Receptor modulators

Neurotrophin mimetics are small molecules or peptide like molecules that can modulate the action of the neurotrophin receptor. One of the main causes of neurodegeneration involves changes in the expression of neurotrophins (NTs) and/or their receptors (TrkA, TrkB, TrkC and p75NTR). Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor pharmacokinetic properties, such as reduced bioavailability and low metabolic stability, the hyperalgesia, the inability to penetrate the blood–brain barrier and the short half-lives render the large neurotrophin proteins not suitable to be implemented as drugs.[1]

For this reason, several efforts have been made to develop neurotrophin mimetics (small molecules and peptidomimetics) that can modulate the action of the neurotrophin receptors (Trks and p75NTR) and possess drug-like pharmacokinetic and pharmacodynamic profiles. Specifically, these mimetics can be classified as TrkA and TrkB receptor agonists and p75NTR modulators/antagonists.[2]

Synthetic small molecule neurotrophin mimetics

TrkA agonists

Among the TrkA agonists, the small molecule gambogic amide exerts a potent neurotrophic activity decreasing apoptosis in primary hippocampal neurons.[3] The non-peptidic TrkA agonist MT2 protects neurons from Aβ amyloid-mediated death in NGF-deficient neurons[4] and talaumidin and its derivatives show neuroprotective effects, promoting neurite outgrowth in PC12 cells.[5] Furthermore, the peptidomimetic cerebrolysin is known for its protective role in Alzheimer’s disease (AD).[6] It was shown to improve the activities of daily living and the psychiatric symptoms in patients with mild to severe form of AD, after intravenous administration in a double-blind trial.[7] In addition, the cyclic peptide tavilermide (MIM-D3), acting as a partial TrkA receptor agonist, showed a relevant improvement of cognitive capacities of treated aged rats, leading to a selective survival of the cholinergic neurons.[8]

A phase 3 clinical trial of 5% and 1% tavilermide ophthalmic solutions for the treatment of dry eye was completed in 2020 (NCT03925727), with positive results concerning safety and efficacy. Recent studies demonstrated the neurotrophic activity of carvacrol by inducing neurite outgrowth and phosphorylation of TrkA in cells deprived of NGF.[9] The same research group investigated the neurotrophic effect of the well-known antibiotic doxycycline and they found that it prevents amyloid toxicity in a Drosophila model of AD both in vitro and in vivo and induces neuritogenesis by activation of TrkA.[10]

Additionally, some novel DHEA derivatives were shown to be TrkA agonists. In particular, the C17-spiroepoxy derivative, BNN-27,[11] induces phosphorylation of TrkA in neuronal and glial cells in culture and it exerts antiapoptotic effect without inducing hyperalgesia.[12] Moreover, it improved memorizing abilities in rats after i.p. administration[13] and restored the myelin loss in cuprizone-induced demyelination in vivo.[14] Moreover, the C17-spirocyclopryl DHEA derivatives, ENT-A010 and ENT-A013, were shown to be potent TrkA agonists.[15][16] In particular, ENT-A010 acts as dual TrkA and TrkB agonist while, ENT-A013 acts as a selective TrkA agonist. Both induce phosphorylation of TrkA and its downstream signaling pathways, and promote cell survival of PC12 cells from serum deprivation. In addition, they exhibit potent neuroprotective effects in dorsal root ganglia and anti-amyloid activity in hippocampal neurons.[15][16]

TrkB agonists

TrkB agonists have received extensive interest from the scientific community resulting in the synthesis and biological evaluation of a large number of mimetics. Deoxygedunin, with a selective TrkB activity, is able to promote axon regeneration in topical treatments.[17] Furthermore, it shows efficacy in two Parkinson's disease (PD) animal models, leading to the protection of locomotor function and the reduction of neuronal death in dopaminergic neurons.[18] A number of studies corroborated that the flavonoid 7,8-Dihydroxyflavone (7,8-DHF) shows neuroprotection in PD and Huntington's disease (HD) models[19][20] together with antioxidant activity[21] and enhancement of motor neuronal survival, motor function and spine density in amyotrophic lateral sclerosis (ALS) model.[22] The benzothiazole riluzole exerts neuroprotective effects by increasing BDNF and GDNF levels with improvement of motor neuron survival. It has been approved for the treatment of ALS and delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months.[23] Furthermore, several combinations of riluzole with other drugs are in clinical trials (NCT02588677, NCT03127267).

Brimonidine exerts neuroprotective effects in retinal ganglion cells (RGCs) through up-regulation of the expression of BDNF in these cells.[24] It is used in the treatment of glaucoma as eye drops to reduce intraocular pressure (IOP) under the brand name Lumify®. Different drugs, used against PD also behave as neurotrophin mimetics such as rotigotine, selegiline, rasagiline, memantine and levodopa interacting with TrkB and increasing BDNF expression.[25] Furthermore, of particular note, the groups of F. Longo and S. Massa discovered small molecule neurotrophic mimetics exhibiting specificity for TrkB at nanomolar concentrations.[26] In particular, LM22A-4, prevents neuronal death in in vitro models of AD, HD and PD.[27]

Among the peptidomimetic TrkB agonists, the dimeric dipeptide GSB-106 showed neurotrophic and neuroprotective effects by specific activation of TrkB and its signaling pathways.[28][29] Furthermore, the tricyclic dimeric peptide TDP6 acts as a TrkB agonist mimicking BDNF and induces autophosphorylation of TrkB in primary oligodendrocyte cultures, leading to oligodendrocyte myelination.[30] Regarding DHEA derivatives, the C17-spiroepoxy analogue, BNN-20, binds with high affinity to TrkB, showing antiapoptotic activity in vitro. Its neuroprotective activity was analyzed in the Weaver mouse genetic model of PD in which long term administration of BNN-20 protects the dopaminergic neurons by mimicking BDNF and induces antiapoptotic, antioxidant and anti-inflammatory effects.[11][31]

p75NTR modulators

In this class it is worthwhile to highlight the small non-peptide molecules LM22A-24 and LM11A-31 developed by Longo and Massa. Through the modulation of p75NTR activity, these compounds downregulate degenerative and upregulate trophic signaling.[32] In particular, LM11A-31 was found to inhibit several pathophysiological mechanisms involved in AD and related to p75NTR.[33][34] Oral administration in AD mice models reduces degeneration of cholinergic neurites.[34] Furthermore, by a direct activation of p75NTR signaling and inhibition of apoptotic pathway, it improves motor function in a spinal cord injury (SCI) mice model and leads to an antiapoptotic effect in mice after traumatic brain injury (TBI).[35][36] In February 2017, a phase 2 clinical trial started focusing on the evaluation of the safety of LM11A-31 in mild to moderate AD (NCT03069014). This study was completed in June 2020, but the results have not been published yet.

Another drug belonging to the class of p75NTR antagonists is THX-B, which inhibits NGF-p75NTR binding and prevents the death of RGCs in axotomy and glaucoma. In addition, in combination with LM22A-24, THX-B delays the loss of retinal structure, prevents RGC degeneration and preserves ganglion cell layer-inner plexiform layer thickness with a better efficacy compared to LM22A-24.[37] Finally, a p75NTR antagonist, EVT901, was able to improve functional outcomes in two models of traumatic brain injury.[38] Furthermore it was found to reduce inflammation in vivo in the TGFAD344 rat model of AD.[39]

Natural neurotrophin mimetics

There are a number of natural products with neurotrophic activity, which results from several mechanisms including enhancing BDNF gene transcription, upregulating the expression of BDNF and TrkB, and extracellular signal-regulated kinase (ERK) and CREB signalling.[40][41][42]

The first discovered non-protein neurotrophic natural product was lactacystin, isolated from a culture broth of Streptomyces sp.[40] Magnolol and honokiol, the main constituents of Magnolia officinalis and Magnolia obovata stem bark, have been reported to have neurotrophic activity in primary cultured rat cortical by enhancing the BDNF expression.[41][42] Merrilactone A, jiadifenin, jiadifenolide, (1R,10S)-2-oxo-3,4-dehydroxyneomajucin, jiadifenoxolane A, (2R)-hydroxynorneomajucin, 11-O-debenzoyltashironin,tricycloillicinone, and bicycloillicinone, natural products of the Illicium family have been shown to promote neurite outgrowth in primary cultures of cortical neurons of fetal rats.[40][41] Neurotrophic properties are also possessed by several members of the Lycopodium alkaloids (huperzine A, lyconadins, complanadine A and B, and nankakurine A and B). Studies have shown that huperazine A can elevate the levels of NGF and BDNF. Synthesis of NGF can be upregulated by administration of cyathanediterpenoids specifically erinacines, scabronines and cyrneines.[40]

Some flavonoids, Isoflavonoids and neoflavonoids were found to have neuroprotective activity. Among the effective flavonoids, luteolin from Lonicera japonica sp., isorhamnetin from Opuntia ficus-indica, genistein from Genista tinctoria, and calycosin from Astragalus membranaceus showed the most promising effects by increasing the mRNA expression and protein secretion of NGF, GDNF, and BDNF.[42] Paecilomycine A and spirotenuipesines A and B, members of the trichothecenes, isolated from the fruiting bodies of Paecilomycestenuipes, have significant neurotrophic profiles especially paecilomycine A which can stimulate the synthesis of neurotrophic factors.[40] Polyprenylatedacylphloroglucinols (PPAPs) represented by hyperforin, hypericin and garsubellin A, have neurotrophic like properties. Hyperforin, isolated from the herb St. John's wort (Hypericum perforatum), can stimulate the upregulation of the TrkB receptor.[40][42]

Beside natural products, there are some small molecules of natural origin that exert neurotrophic activities such as: Panaxytriol (promotes NGF-induced neurite outgrowth in PC-12 cells); 7,8-dihydroxyflavone (TrkB activator); Deoxygedunin (BDNF mimetic); Kansuinin E (promotes neurotrophic activity, most likely through TrkA activation); Tripchlorolide (stimulates expression of BDNF mRNA); Fucoxanthin (increases BDNF production and activates PKA/CREB pathway); Silibinin (Activate hippocampal ROS-BDNF-TrkB patway).[40][42]

References

  1. ↑ Josephy-Hernandez, Sylvia; Jmaeff, Sean; Pirvulescu, Iulia; Aboulkassim, Tahar; Saragovi, H. Uri (January 2017). "Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm". Neurobiology of Disease 97 (Pt B): 139–155. doi:10.1016/j.nbd.2016.08.004. ISSN 0969-9961. PMID 27546056. http://dx.doi.org/10.1016/j.nbd.2016.08.004. 
  2. ↑ Gudasheva, Tatiana A.; Povarnina, Polina Y.; Tarasiuk, Aleksey V.; Seredenin, Sergey B. (September 2021). "Low‐molecular mimetics of nerve growth factor and brain‐derived neurotrophic factor: Design and pharmacological properties" (in en). Medicinal Research Reviews 41 (5): 2746–2774. doi:10.1002/med.21721. ISSN 0198-6325. PMID 32808322. https://onlinelibrary.wiley.com/doi/10.1002/med.21721. 
  3. ↑ Jang, Sung-Wuk; Okada, Masashi; Sayeed, Iqbal; Xiao, Ge; Stein, Donald; Jin, Peng; Ye, Keqiang (2007-10-09). "Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death". Proceedings of the National Academy of Sciences 104 (41): 16329–16334. doi:10.1073/pnas.0706662104. ISSN 0027-8424. PMID 17911251. 
  4. ↑ Scarpi, D; Cirelli, D; Matrone, C; Castronovo, G; Rosini, P; Occhiato, E G; Romano, F; Bartali, L et al. (July 2012). "Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity". Cell Death & Disease 3 (7): e339. doi:10.1038/cddis.2012.80. ISSN 2041-4889. PMID 22764098. PMC 3406579. http://dx.doi.org/10.1038/cddis.2012.80. 
  5. ↑ Harada, Kenichi; Kubo, Miwa; Fukuyama, Yoshiyasu (2020-04-23). "Chemistry and Neurotrophic Activities of (–)-Talaumidin and Its Derivatives". Frontiers in Chemistry 8: 301. doi:10.3389/fchem.2020.00301. ISSN 2296-2646. PMID 32391327. 
  6. ↑ Alvarez, X. A.; Cacabelos, R.; Laredo, M.; Couceiro, V.; Sampedro, C.; Varela, M.; Corzo, L.; Fernandez-Novoa, L. et al. (January 2006). "A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer's disease". European Journal of Neurology 13 (1): 43–54. doi:10.1111/j.1468-1331.2006.01222.x. ISSN 1351-5101. PMID 16420392. http://dx.doi.org/10.1111/j.1468-1331.2006.01222.x. 
  7. ↑ Alvarez, X. A.; Cacabelos, R.; Sampedro, C.; Aleixandre, M.; Linares, C.; Granizo, E.; Doppler, E.; Moessler, H. (2010-12-15). "Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimer's disease: results of a randomized, double-blind, controlled trial investigating three dosages of Cerebrolysin". European Journal of Neurology 18 (1): 59–68. doi:10.1111/j.1468-1331.2010.03092.x. ISSN 1351-5101. PMID 20500802. http://dx.doi.org/10.1111/j.1468-1331.2010.03092.x. 
  8. ↑ Bruno, M. A. (2004-09-15). "Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA". Journal of Neuroscience 24 (37): 8009–8018. doi:10.1523/jneurosci.1508-04.2004. ISSN 0270-6474. PMID 15371501. PMC 6729798. http://dx.doi.org/10.1523/jneurosci.1508-04.2004. 
  9. ↑ Sisti, Flávia Malvestio; dos Santos, Neife Aparecida Guinaim; do Amaral, Lilian; dos Santos, Antonio Cardozo (2021-03-05). "The Neurotrophic-Like Effect of Carvacrol: Perspective for Axonal and Synaptic Regeneration". Neurotoxicity Research 39 (3): 886–896. doi:10.1007/s12640-021-00341-1. ISSN 1029-8428. PMID 33666886. http://dx.doi.org/10.1007/s12640-021-00341-1. 
  10. ↑ Costa, Rita; Speretta, Elena; Crowther, Damian C.; Cardoso, Isabel (December 2011). "Testing the Therapeutic Potential of Doxycycline in a Drosophila melanogaster Model of Alzheimer Disease". Journal of Biological Chemistry 286 (48): 41647–41655. doi:10.1074/jbc.m111.274548. ISSN 0021-9258. PMID 21998304. 
  11. ↑ 11.0 11.1 Calogeropoulou, Theodora; Avlonitis, Nicolaos; Minas, Vassilios; Alexi, Xanthippi; Pantzou, Athanasia; Charalampopoulos, Ioannis; Zervou, Maria; Vergou, Varvara et al. (2009-10-21). "Novel Dehydroepiandrosterone Derivatives with Antiapoptotic, Neuroprotective Activity". Journal of Medicinal Chemistry 52 (21): 6569–6587. doi:10.1021/jm900468p. ISSN 0022-2623. PMID 19845386. http://dx.doi.org/10.1021/jm900468p. 
  12. ↑ Pediaditakis, Iosif; Efstathopoulos, Paschalis; Prousis, Kyriakos C.; Zervou, Maria; Arévalo, Juan Carlos; Alexaki, Vasileia I.; Nikoletopoulou, Vassiliki; Karagianni, Efthymia et al. (December 2016). "Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation". Neuropharmacology 111: 266–282. doi:10.1016/j.neuropharm.2016.09.007. ISSN 0028-3908. PMID 27618740. http://dx.doi.org/10.1016/j.neuropharm.2016.09.007. 
  13. ↑ Pitsikas, Nikolaos; Gravanis, Achille (April 2017). "The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts delay-dependent and scopolamine-induced recognition memory deficits in rats". Neurobiology of Learning and Memory 140: 145–153. doi:10.1016/j.nlm.2017.03.004. ISSN 1074-7427. PMID 28274826. http://dx.doi.org/10.1016/j.nlm.2017.03.004. 
  14. ↑ Bonetto, Giulia; Charalampopoulos, Ioannis; Gravanis, Achille; Karagogeos, Domna (2017-06-01). "The novel synthetic microneurotrophin BNN27 protects mature oligodendrocytes against cuprizone-induced death, through the NGF receptor TrkA". Glia 65 (8): 1376–1394. doi:10.1002/glia.23170. ISSN 0894-1491. PMID 28567989. http://dx.doi.org/10.1002/glia.23170. 
  15. ↑ 15.0 15.1 Yilmaz, Canelif; Rogdakis, Thanasis; Latorrata, Alessia; Thanou, Evangelia; Karadima, Eleftheria; Papadimitriou, Eleni; Siapi, Eleni; Li, Ka Wan et al. (2022-03-09). "ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses". Biomolecules 12 (3): 424. doi:10.3390/biom12030424. ISSN 2218-273X. PMID 35327616. 
  16. ↑ 16.0 16.1 Rogdakis, Thanasis; Charou, Despoina; Latorrata, Alessia; Papadimitriou, Eleni; Tsengenes, Alexandros; Athanasiou, Christina; Papadopoulou, Marianna; Chalikiopoulou, Constantina et al. (2022-03-06). "Development and Biological Characterization of a Novel Selective TrkA Agonist with Neuroprotective Properties against Amyloid Toxicity". Biomedicines 10 (3): 614. doi:10.3390/biomedicines10030614. ISSN 2227-9059. PMID 35327415. 
  17. ↑ English, Arthur W.; Liu, Kevin; Nicolini, Jennifer M.; Mulligan, Amanda M.; Ye, Keqiang (2013-09-16). "Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves". Proceedings of the National Academy of Sciences 110 (40): 16217–16222. doi:10.1073/pnas.1303646110. ISSN 0027-8424. PMID 24043773. 
  18. ↑ Nie, Shuke; Xu, Yan; Chen, Guiqin; Ma, Kai; Han, Chao; Guo, Zhenli; Zhang, Zhentao; Ye, Keqiang et al. (December 2015). "Small molecule TrkB agonist deoxygedunin protects nigrostriatal dopaminergic neurons from 6-OHDA and MPTP induced neurotoxicity in rodents". Neuropharmacology 99: 448–458. doi:10.1016/j.neuropharm.2015.08.016. ISSN 0028-3908. PMID 26282118. http://dx.doi.org/10.1016/j.neuropharm.2015.08.016. 
  19. ↑ Jang, Sung-Wuk; Liu, Xia; Yepes, Manuel; Shepherd, Kennie R.; Miller, Gary W.; Liu, Yang; Wilson, W. David; Xiao, Ge et al. (2010-01-25). "A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone". Proceedings of the National Academy of Sciences 107 (6): 2687–2692. doi:10.1073/pnas.0913572107. ISSN 0027-8424. PMID 20133810. 
  20. ↑ Jiang, M.; Peng, Q.; Liu, X.; Jin, J.; Hou, Z.; Zhang, J.; Mori, S.; Ross, C. A. et al. (2013-02-27). "Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington's disease". Human Molecular Genetics 22 (12): 2462–2470. doi:10.1093/hmg/ddt098. ISSN 0964-6906. PMID 23446639. PMC 3658168. http://dx.doi.org/10.1093/hmg/ddt098. 
  21. ↑ Chen, Jing; Chua, Kao-Wei; Chua, Chu C.; Yu, Hailong; Pei, Aijie; Chua, Balvin H.L.; Hamdy, Ronald C.; Xu, Xingshun et al. (July 2011). "Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity". Neuroscience Letters 499 (3): 181–185. doi:10.1016/j.neulet.2011.05.054. ISSN 0304-3940. PMID 21651962. http://dx.doi.org/10.1016/j.neulet.2011.05.054. 
  22. ↑ Korkmaz, Orhan Tansel; Aytan, Nurgul; Carreras, Isabel; Choi, Ji-Kyung; Kowall, Neil W.; Jenkins, Bruce G.; Dedeoglu, Alpaslan (April 2014). "7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis". Neuroscience Letters 566: 286–291. doi:10.1016/j.neulet.2014.02.058. ISSN 0304-3940. PMID 24637017. PMC 5906793. http://dx.doi.org/10.1016/j.neulet.2014.02.058. 
  23. ↑ Dennys, Cassandra N.; Armstrong, JeNay; Levy, Mark; Byun, Youn Jung; Ramdial, Kristina R.; Bott, Marga; Rossi, Fabian H.; Fernández-Valle, Cristina et al. (September 2015). "Chronic inhibitory effect of riluzole on trophic factor production". Experimental Neurology 271: 301–307. doi:10.1016/j.expneurol.2015.05.016. ISSN 0014-4886. PMID 26071088. PMC 4864959. http://dx.doi.org/10.1016/j.expneurol.2015.05.016. 
  24. ↑ Gao, Hua (2002-06-01). "Up-regulation of Brain-Derived Neurotrophic Factor Expression by Brimonidine in Rat Retinal Ganglion Cells". Archives of Ophthalmology 120 (6): 797–803. doi:10.1001/archopht.120.6.797. ISSN 0003-9950. PMID 12049586. http://dx.doi.org/10.1001/archopht.120.6.797. 
  25. ↑ Jin (2020-01-17). "Regulation of BDNF-TrkB Signaling and Potential Therapeutic Strategies for Parkinson's Disease". Journal of Clinical Medicine 9 (1): 257. doi:10.3390/jcm9010257. ISSN 2077-0383. PMID 31963575. 
  26. ↑ Massa, Stephen M.; Yang, Tao; Xie, Youmei; Shi, Jian; Bilgen, Mehmet; Joyce, Jeffrey N.; Nehama, Dean; Rajadas, Jayakumar et al. (2010-05-03). "Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents". Journal of Clinical Investigation 120 (5): 1774–1785. doi:10.1172/jci41356. ISSN 0021-9738. PMID 20407211. PMC 2860903. http://dx.doi.org/10.1172/jci41356. 
  27. ↑ Longo, Frank M.; Massa, Stephen M. (July 2013). "Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease". Nature Reviews Drug Discovery 12 (7): 507–525. doi:10.1038/nrd4024. ISSN 1474-1776. PMID 23977697. http://dx.doi.org/10.1038/nrd4024. 
  28. ↑ Gudasheva, T. A.; Logvinov, I. O.; Antipova, T. A.; Seredenin, S. B. (July 2013). "Brain-derived neurotrophic factor loop 4 dipeptide mimetic GSB-106 activates TrkB, Erk, and Akt and promotes neuronal survival in vitro". Doklady Biochemistry and Biophysics 451 (1): 212–214. doi:10.1134/s1607672913040121. ISSN 1607-6729. PMID 23975404. http://dx.doi.org/10.1134/s1607672913040121. 
  29. ↑ Zainullina, L. F.; Vakhitova, Yu. V.; Lusta, A. Yu.; Gudasheva, T. A.; Seredenin, S. B. (2021-04-08). "Dimeric mimetic of BDNF loop 4 promotes survival of serum-deprived cell through TrkB-dependent apoptosis suppression". Scientific Reports 11 (1): 7781. doi:10.1038/s41598-021-87435-0. ISSN 2045-2322. PMID 33833366. PMC 8032782. http://dx.doi.org/10.1038/s41598-021-87435-0. 
  30. ↑ Wong, Agnes W.; Giuffrida, Lauren; Wood, Rhiannon; Peckham, Haley; Gonsalvez, David; Murray, Simon S.; Hughes, Richard A.; Xiao, Junhua (November 2014). "TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination". Molecular and Cellular Neuroscience 63: 132–140. doi:10.1016/j.mcn.2014.10.002. ISSN 1044-7431. PMID 25461619. http://dx.doi.org/10.1016/j.mcn.2014.10.002. 
  31. ↑ Botsakis, Konstantinos; Mourtzi, Theodora; Panagiotakopoulou, Vasiliki; Vreka, Malamati; Stathopoulos, Georgios T.; Pediaditakis, Iosif; Charalampopoulos, Ioannis; Gravanis, Achilleas et al. (July 2017). "BNN-20, a synthetic microneurotrophin, strongly protects dopaminergic neurons in the "weaver" mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor". Neuropharmacology 121: 140–157. doi:10.1016/j.neuropharm.2017.04.043. ISSN 0028-3908. PMID 28461162. http://dx.doi.org/10.1016/j.neuropharm.2017.04.043. 
  32. ↑ Massa, S. M. (2006-05-17). "Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death". Journal of Neuroscience 26 (20): 5288–5300. doi:10.1523/jneurosci.3547-05.2006. ISSN 0270-6474. PMID 16707781. PMC 6675309. http://dx.doi.org/10.1523/jneurosci.3547-05.2006. 
  33. ↑ Yang, Tao; Knowles, Juliet K.; Lu, Qun; Zhang, Hong; Arancio, Ottavio; Moore, Laura A.; Chang, Timothy; Wang, Qian et al. (2008-11-03). "Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment". PLOS ONE 3 (11): e3604. doi:10.1371/journal.pone.0003604. ISSN 1932-6203. PMID 18978948. 
  34. ↑ 34.0 34.1 Simmons, Danielle A.; Knowles, Juliet K.; Belichenko, Nadia P.; Banerjee, Gargi; Finkle, Carly; Massa, Stephen M.; Longo, Frank M. (2014-08-25). "A Small Molecule p75NTR Ligand, LM11A-31, Reverses Cholinergic Neurite Dystrophy in Alzheimer's Disease Mouse Models with Mid- to Late-Stage Disease Progression". PLOS ONE 9 (8): e102136. doi:10.1371/journal.pone.0102136. ISSN 1932-6203. PMID 25153701. 
  35. ↑ "Correction: Tep et al., Oral Administration of a Small Molecule Targeted to Block proNGF Binding to p75 Promotes Myelin Sparing and Functional Recovery after Spinal Cord Injury". Journal of Neuroscience 34 (5): 2012.2–2012. 2014-01-29. doi:10.1523/jneurosci.0054-14.2014. ISSN 0270-6474. PMC 4081475. http://dx.doi.org/10.1523/jneurosci.0054-14.2014. 
  36. ↑ Shi, Jian; Longo, Frank M.; Massa, Stephen M. (2013-11-01). "A small molecule p75NTR ligand protects neurogenesis after traumatic brain injury". Stem Cells 31 (11): 2561–2574. doi:10.1002/stem.1516. ISSN 1066-5099. PMID 23940017. 
  37. ↑ Bai, Yujing; Dergham, Pauline; Nedev, Hinyu; Xu, Jing; Galan, Alba; Rivera, Jose Carlos; ZhiHua, Shi; Mehta, Hrishikesh M. et al. (December 2010). "Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism". Journal of Biological Chemistry 285 (50): 39392–39400. doi:10.1074/jbc.m110.147801. ISSN 0021-9258. PMID 20943663. 
  38. ↑ Delbary-Gossart, Sandrine; Lee, Sangmi; Baroni, Marco; Lamarche, Isabelle; Arnone, Michele; Canolle, Benoit; Lin, Amity; Sacramento, Jeffrey et al. (2016-04-15). "A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury". Brain 139 (6): 1762–1782. doi:10.1093/brain/aww074. ISSN 0006-8950. PMID 27084575. PMC 4892754. http://dx.doi.org/10.1093/brain/aww074. 
  39. ↑ Lee, Sangmi; Mattingly, Aaron; Lin, Amity; Sacramento, Jeffrey; Mannent, Leda; Castel, Marie-Noelle; Canolle, Benoit; Delbary-Gossart, Sandrine et al. (2016-04-22). "A novel antagonist of p75NTR reduces peripheral expansion and CNS trafficking of pro-inflammatory monocytes and spares function after traumatic brain injury". Journal of Neuroinflammation 13 (1): 88. doi:10.1186/s12974-016-0544-4. ISSN 1742-2094. PMID 27102880. 
  40. ↑ 40.0 40.1 40.2 40.3 40.4 40.5 40.6 Xu, Jing; Lacoske, Michelle H.; Theodorakis, Emmanuel A. (2013-12-18). "Neurotrophic Natural Products: Chemistry and Biology". Angewandte Chemie International Edition 53 (4): 956–987. doi:10.1002/anie.201302268. ISSN 1433-7851. PMID 24353244. PMC 3945720. http://dx.doi.org/10.1002/anie.201302268. 
  41. ↑ 41.0 41.1 41.2 Bawari, Sweta; Tewari, Devesh; Argüelles, Sandro; Sah, Archana N.; Nabavi, Seyed Fazel; Xu, Suowen; Vacca, Rosa Anna; Nabavi, Seyed Mohammad et al. (October 2019). "Targeting BDNF signaling by natural products: Novel synaptic repair therapeutics for neurodegeneration and behavior disorders". Pharmacological Research 148: 104458. doi:10.1016/j.phrs.2019.104458. ISSN 1043-6618. PMID 31546015. http://dx.doi.org/10.1016/j.phrs.2019.104458. 
  42. ↑ 42.0 42.1 42.2 42.3 42.4 Fukuyama, Yoshiyasu; Kubo, Miwa; Harada, Kenichi (September 2020). "The search for, and chemistry and mechanism of, neurotrophic natural products" (in en). Journal of Natural Medicines 74 (4): 648–671. doi:10.1007/s11418-020-01431-8. ISSN 1340-3443. PMID 32643028. 



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