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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Perspective

Can Brain-derived Neurotrophic Factor (BDNF) Mimetics be a Way Out for Neurodegenerative Diseases?

Author(s): Orhan Tansel Korkmaz*

Volume 29, Issue 4, 2023

Published on: 03 February, 2023

Page: [246 - 250] Pages: 5

DOI: 10.2174/1381612829666230127142414

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Abstract

Neurodegenerative diseases are chronic and progressive disease groups characterized by the decline of neural transmission because of the loss of structure and function of neurons. Although there is currently no effective treatment for neurodegenerative diseases, new treatment strategies need to be developed urgently. Among neurotrophins, BDNF has been extensively investigated, and it has emerged as an important regulator of synaptic plasticity, neuronal survival, and differentiation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases. Moreover, promising results have been obtained for BDNF in many experimental studies on animal models. In addition, BDNF serves as a crucial molecular target for developing drugs to treat neurological diseases. However, several pharmacokinetic difficulties have limited its use in clinical practice, such as its inability to cross the blood-brain barrier, short half-life, and potential adverse effects. To avoid these difficulties, several approaches have been explored, but they have led to disappointing results. One way to overcome the limitations of BDNF may be with mimetic molecules that can effectively stimulate the receptors it has an affinity with and thus activates BDNF pathways. In this perspective article, an evaluation of the efficacy of different BDNF mimetics against neurodegenerative diseases was made.

Keywords: Neurodegenerative diseases, neurotrophins, brain-derived neurotrophic factor, BDNF mimetics, TrkB, p75NTR, BBB.

[1]
Kumar B, Sharma D. Recent patent advances for neurodegenerative disorders and its treatment. Recent Pat Drug Deliv Formul 2017; 11(3): 158-72.
[2]
Dugger BN, Dickson DW. Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol 2017; 9(7): a028035.
[http://dx.doi.org/10.1101/cshperspect.a028035]
[3]
Scott-Solomon E, Kuruvilla R. Mechanisms of neurotrophin trafficking via Trk receptors. Mol Cell Neurosci 2018; 91: 25-33.
[http://dx.doi.org/10.1016/j.mcn.2018.03.013]
[4]
Kowiański P, Lietzau G, Czuba E, Waśkow M, Steliga A, Moryś J. BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol 2018; 38(3): 579-93.
[http://dx.doi.org/10.1007/s10571-017-0510-4]
[5]
Chiavacci E, Terzibasi Tozzini E, Fairuz Azman K, Zakaria R. Recent advances on the role of brain-derived neurotrophic factor (BDNF). Neurodegener Dis 2022; 33(12): 6827.
[6]
Khalin I, Alyautdin R, Kocherga G, Abu Bakar M. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness Int J Nanomedicine 2015; 10: 3245-67.
[http://dx.doi.org/10.2147/IJN.S77480]
[7]
Szarowicz CA, Steece-Collier K, Caulfield ME. New frontiers in neurodegeneration and regeneration associated with brain-derived neurotrophic factor and the rs6265 single nucleotide polymorphism. Int J Mol Sci 2022; 23(14): 8011.
[http://dx.doi.org/10.3390/ijms23148011]
[8]
Gudasheva TA. Design and synthesis of dipeptide mimetics of brain-derived neurotrophic factor. Bioorg Khim 2012; 38(3): 280-90.
[9]
Robinson RC, Choe S, Radziejewski C, et al. The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci 1999; 8(12): 2589-97.
[10]
Du X, Hill RA. 7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders. Neurochem Int 2015; 89: 170-80.
[11]
Gudasheva TA, Logvinov IO. Dipeptide mimetics of different NGF and BDNF loops activate PLC-γ1. Dokl Biochem Biophys 2020; 494(1): 244-7.
[12]
Zainullina LF. Dimeric mimetic of BDNF loop 4 promotes survival of serum-deprived cell through TrkB-dependent apoptosis suppression. Sci Rep 2021; 11(1): 7781.
[13]
Gudasheva TA, Povarnina P, Logvinov IO, Antipova TA, Seredenin SB. Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats. Drug Des Devel Ther 2016; 10: 3545-53.
[http://dx.doi.org/10.2147/DDDT.S118768]
[14]
Xiao J, Hughes RA, Lim JY. A small peptide mimetic of brain-derived neurotrophic factor promotes peripheral myelination. J Neurochem 2013; 125(3): 386-98.
[http://dx.doi.org/10.1111/jnc.12168]
[15]
Wong AW, Giuffrida L, Wood R, et al. TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination. Mol Cell Neurosci 2014; 63: 132-40.
[16]
Massa SM, Yang T, Xie Y, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest 2010; 120(5): 1774-85.
[http://dx.doi.org/10.1172/JCI41356]
[17]
Simmons DA, Belichenko NP, Yang T, et al. A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington’s disease. J Neurosci 2013; 33(48): 18712-2.
[18]
Li W, Bellot-Saez A, Phillips ML, Yang T, Longo FM, Pozzo-Miller L. A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object location memory in Rett syndrome mice. Dis Model Mech 2017; 10(7): 837-45.
[http://dx.doi.org/10.1242/dmm.029959]
[19]
Fletcher JL, Dill LK, Wood RJ, et al. Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury. Exp Neurol 2021; 339: 113652.
[http://dx.doi.org/10.1016/j.expneurol.2021.113652]
[20]
Yu G, Wang W. Protective effects of LM22A-4 on injured spinal cord nerves. Int J Clin Exp Pathol 2015; 8(6): 6526-32.
[21]
Gu F, Parada I, Yang T, Longo FM, Prince DA. Chronic partial TrkB activation reduces seizures and mortality in a mouse model of Dravet syndrome. Proc Natl Acad Sci USA 2022; 119(7): e2022726119.
[http://dx.doi.org/10.1073/pnas.2022726119]
[22]
Chakravarthy B, Gaudet C, Ménard M, et al. Amyloid-beta peptides stimulate the expression of the p75(NTR) neurotrophin receptor in SHSY5Y human neuroblastoma cells and AD transgenic mice. J Alzheimers Dis 2010; 19(3): 915-25.
[23]
Hu XY, Zhang HY, Qin S, Xu H, Swaab DF, Zhou JN. Increased p75(NTR) expression in hippocampal neurons containing hyperphosphorylated tau in Alzheimer patients. Exp Neurol 2002; 178(1): 104-1.
[http://dx.doi.org/10.1006/exnr.2002.8018]
[24]
Simmons DA, Knowles JK, Belichenko NP, et al. 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 2014; 9(8): e102136.
[25]
Krishnan N, Krishnan K, Connors CR, et al. PTP1B inhibition suggests a therapeutic strategy for Rett syndrome. J Clin Invest 2015; 125(8): 3163-77.
[26]
Chiu Y-J, Lin T-H, Chang K-H, et al. Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity. Aging 2022; 14(18): 7568-86.
[http://dx.doi.org/10.18632/aging.204306]
[27]
Zhang Z, Liu X, Schroeder JP, et al. 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 2014; 39(3): 638-50.
[28]
Aytan N, Choi JK, Carreras I, et al. Protective effects of 7,8-Dihydroxyflavone on neuropathological and neurochemical changes in a mouse model of Alzheimer’s disease. Eur J Pharmacol 2018; 828: 9-17.
[29]
Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM. 7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss. PLoS One 2014; 9(3): e91453.
[30]
Luo D, Shi Y, Wang J, et al. 7,8-Dihydroxyflavone protects 6-OHDA and MPTP induced dopaminergic neurons degeneration through activation of TrkB in rodents. Neurosci Lett 2016; 620: 43-9.
[31]
Sconce MD, Churchill MJ, Moore C, Meshul CK. Intervention with 7,8-dihydroxyflavone blocks further striatal terminal loss and restores motor deficits in a progressive mouse model of Parkinson’s disease. Neuroscience 2015; 290: 454-71.
[32]
Nie S, Ma K, Sun M, et al. 7,8-Dihydroxyflavone protects nigrostriatal dopaminergic neurons from rotenone-induced neurotoxicity in rodents. Parkinsons Dis 2019; 2019: 9193534.
[33]
Barriga GGD, Giralt A, Anglada-Huguet M, et al. 7,8-Dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington’s disease mouse model through specific activation of the PLCγ1 pathway. Hum Mol Genet 2017; 26(16): 3144-60.
[34]
Jiang M, Peng Q, Liu X, et al. Small- molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington’s disease. Hum Mol Genet 2013; 22(12): 2462-70.
[http://dx.doi.org/10.1093/hmg/ddt098]
[35]
Korkmaz OT, Aytan N, Carreras I, et al. 7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis. Neurosci Lett 2014; 566: 286-91.
[36]
Paul R, Nath J, Paul S, et al. Suggesting 7,8-dihydroxyflavone as a promising nutraceutical against CNS disorder. Neurochem Int 2021; 148: 105068.
[37]
Brinkley G, Nam H, Shim E, et al. Restoration of motor learning in a mouse model of Rett syndrome following long-term treatment with a novel small-molecule activator of TrkB. Dis Model Mech 2020; 13(11): dmm044685.
[38]
Chen C, Ahn EH, Liu X, et al. Optimized TrkB agonist ameliorates Alzheimer’s disease pathologies and improves cognitive functions via inhibiting delta-secretase. ACS Chem Neurosci 2021; 12(13): 2448-61.
[http://dx.doi.org/10.1021/acschemneuro.1c00181]
[39]
Liu X, Chan CB, Jang SW, et al. A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect. J Med Chem 2010; 53(23): 8274-6.

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