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Licensed Unlicensed Requires Authentication Published online by De Gruyter November 8, 2021

Emphasizing roles of BDNF promoters and inducers in Alzheimer's disease for improving impaired cognition and memory

Madhuparna Banerjee and Rekha R. Shenoy

Abstract

Brain-derived neurotrophic factor (BDNF) is a crucial neurotrophic factor adding to neurons’ development and endurance. The amount of BDNF present in the brain determines susceptibility to various neurodegenerative diseases. In Alzheimer’s disease (AD), often it is seen that low levels of BDNF are present, which primarily contributes to cognition deficit by regulating long-term potentiation (LTP) and synaptic plasticity. Molecular mechanisms underlying the synthesis, storage and release of BDNF are widely studied. New molecules are found, which contribute to the signal transduction pathway. Two important receptors of BDNF are TrkB and p75NTR. When BDNF binds to the TrkB receptor, it activates three main signalling pathways-phospholipase C, MAPK/ERK, PI3/AKT. BDNF holds an imperative part in LTP and dendritic development, which are essential for memory formation. BDNF supports synaptic integrity by influencing LTP and LTD. This action is conducted by modulating the glutamate receptors; AMPA and NMDA. This review paper discusses the aforesaid points along with inducers of BDNF. Drugs and herbals promote neuroprotection by increasing the hippocampus’ BDNF level in various disease-induced animal models for neurodegeneration. Advancement in finding pertinent molecules contributing to the BDNF signalling pathway has been discussed, along with the areas that require further research and study.


Corresponding author: Rekha R. Shenoy, Associate Professor, Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, MadhavNagar, Manipal 576104, Udupi District, Karnataka, India, Phone: 91-820-2922482, 91-820-2922433, Fax: 91-820-2571998, E-mail:

Acknowledgments

Authors acknowledge BioRender.com for creation of figures incorporated in the review article.

  1. Research funding: Not applicable.

  2. Author contributions: Authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

References

1. Mantzavinos, V, Alexiou, A. Biomarkers for Alzheimer’s disease diagnosis. Curr Alzheimer Res 2017;14:1149–54. https://doi.org/10.2174/1567205014666170203125942.Search in Google Scholar

2. Bronzuoli, MR, Iacomino, A, Steardo, L, Scuderi, C. Targeting neuroinflammation in Alzheimer’s disease. J Inflamm Res 2016;9:199–208. https://doi.org/10.2147/jir.s86958.Search in Google Scholar

3. Gilbert, BJ. The role of amyloid β in the pathogenesis of Alzheimer’s disease. J Clin Pathol 2013;66:362–6. https://doi.org/10.1136/jclinpath-2013-201515.Search in Google Scholar

4. Haass, C, Kaether, C, Thinakaran, G, Sisodia, S. Trafficking and proteolytic processing of APP. Cold Spring Harbor Perspect Med 2012;2:a006270. https://doi.org/10.1101/cshperspect.a006270.Search in Google Scholar

5. Novo, M, Freire, S, Al-Soufi, W. Critical aggregation concentration for the formation of early Amyloid-β (1–42) oligomers. Sci Rep 2018;8:1–8. https://doi.org/10.1038/s41598-018-19961-3.Search in Google Scholar

6. Ciudad, S, Puig, E, Botzanowski, T, Meigooni, M, Arango, AS, Do, J, et al.. Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage. Nat Commun 2020;11:1–14. https://doi.org/10.1038/s41467-020-16566-1.Search in Google Scholar

7. Bathina, S, Das, UN. Brain-derived neurotrophic factor and its clinical Implications. Arch Med Sci 2015;11:1164–78. https://doi.org/10.5114/aoms.2015.56342.Search in Google Scholar

8. 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;38:579–93. https://doi.org/10.1007/s10571-017-0510-4.Search in Google Scholar

9. Baydyuk, M, Xu, B. BDNF signaling and survival of striatal neurons. Front Cell Neurosci 2014;8:1–10. https://doi.org/10.3389/fncel.2014.00254.Search in Google Scholar

10. Connor, B, Young, D, Yan, Q, Faull, RLM, Synek, B, Dragunow, M. Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Mol Brain Res 1997;49:71–81. https://doi.org/10.1016/s0169-328x(97)00125-3.Search in Google Scholar

11. Cattaneo, A, Cattane, N, Pariante, C, Begni, V, Riva, M. The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders. Transl Psychiatry 2016;6:1–10. https://doi.org/10.1038/tp.2016.214.Search in Google Scholar

12. Caffino, L, Mottarlini, F, Fumagalli, F. Born to protect: leveraging BDNF against cognitive deficit in Alzheimer’s disease. CNS Drugs 2020;34:281–97. https://doi.org/10.1007/s40263-020-00705-9.Search in Google Scholar

13. Huang, EJ, Reichardt, LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001;24:677–736. https://doi.org/10.1146/annurev.neuro.24.1.677.Search in Google Scholar

14. Rafieva, LM, Gasanov, E. Neurotrophin propeptides: biological functions and molecular mechanisms. Curr Protein Pept Sci 2016;17:298–305.10.2174/1389203716666150623104145Search in Google Scholar

15. Capsoni, S, Amato, G, Vignone, D, Criscuolo, C, Nykjaer, A, Cattaneo, A. Dissecting the role of sortilin receptor signaling in neurodegeneration induced by NGF deprivation. Biochem Biophys Res Commun 2013;431:579–85. https://doi.org/10.1016/j.bbrc.2013.01.007.Search in Google Scholar

16. Lou, H, Kim, SK, Zaitsev, E, Snell, CR, Lu, B, Loh, YP. Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase E. Neuron 2005;45:245–55. https://doi.org/10.1016/j.neuron.2004.12.037.Search in Google Scholar

17. Egan, MF, Kojima, M, Callicott, JH, Goldberg, TE, Kolachana, BS, Bertolino, A, et al.. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003;112:257–69. https://doi.org/10.1016/s0092-8674(03)00035-7.Search in Google Scholar

18. Yang, B, Ren, Q, Zhang, JC, Chen, QX, Hashimoto, K. Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain–liver axis. Transl Psychiatry 2017;7:1–7. https://doi.org/10.1038/tp.2017.95.Search in Google Scholar PubMed PubMed Central

19. Dieni, S, Matsumoto, T, Dekkers, M, Rauskolb, S, Ionescu, MS, Deogracias, R, et al.. BDNF and its pro-peptide are stored in presynaptic dense core vesicles in brain neurons. J Cell Biol 2012;196:775–88. https://doi.org/10.1083/jcb.201201038.Search in Google Scholar PubMed PubMed Central

20. Mizui, T, Ohira, K, Kojima, M. BDNF pro-peptide: A novel synaptic modulator generated as an N-terminal fragment from the BDNF precursor by proteolytic processing. Neural Regen Res 2017;12:1024–7.10.4103/1673-5374.211173Search in Google Scholar PubMed PubMed Central

21. Klein, R, Smeyne, RJ, Wurst, W, Long, LK, Auerbach, BA, Joyner, AL, et al.. Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 1993;75:113–22. https://doi.org/10.1016/s0092-8674(05)80088-1.Search in Google Scholar

22. Pawson, T, Gish, GD. SH2 and SH3 domains: from structure to function. Cell 1992;71. https://doi.org/10.1016/0092-8674(92)90504-6.Search in Google Scholar

23. Garraway, SM, Huie, JR. Spinal plasticity and behavior: BDNF-induced neuromodulation in uninjured and injured spinal cord. Neural Plast 2016;2016:1–19. https://doi.org/10.1155/2016/9857201.Search in Google Scholar

24. Yoshii, A, Constantine-Paton, M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 2010;70:304–22. https://doi.org/10.1002/dneu.20765.Search in Google Scholar

25. Zirrgiebel, U, Ohga, Y, Carter, B, Berninger, B, Inagaki, N, Thoenen, H, et al.. Characterization of TrkB receptor‐mediated signaling pathways in rat cerebellar granule neurons: involvement of protein kinase C in neuronal survival. J Neurochem 1995;65:2241–50. https://doi.org/10.1046/j.1471-4159.1995.65052241.x.Search in Google Scholar

26. Finkbeiner, S, Tavazoie, SF, Maloratsky, A, Jacobs, KM, Harris, KM, Greenberg, ME. CREB: a major mediator of neuronal neurotrophin responses. Neuron 1997;19:1031–47. https://doi.org/10.1016/s0896-6273(00)80395-5.Search in Google Scholar

27. Huang, EJ, Reichardt, LF. Trk receptors: roles in neuronal signal transduction. Ann Rev Biochem 2003;72:609–42. https://doi.org/10.1146/annurev.biochem.72.121801.161629.Search in Google Scholar PubMed

28. Yamada, M, Ohnishi, H, Sano, SI, Nakatani, A, Ikeuchi, T, Hatanaka, H. Insulin receptor substrate (IRS)-1 and IRS-2 are tyrosine-phosphorylated and associated with phosphatidylinositol 3-kinase in response to brain-derived neurotrophic factor in cultured cerebral cortical neurons. J Biol Chem 1997;272:30334–9. https://doi.org/10.1074/jbc.272.48.30334.Search in Google Scholar PubMed

29. Sarbassov, DD, Ali, SM, Sabatini, DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005;17:596–603. https://doi.org/10.1016/j.ceb.2005.09.009.Search in Google Scholar PubMed

30. Fayard, B, Loeffler, S, Weis, J, Vögelin, E, Krüttgen, A. The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC. J Neurosci Res 2005;80:18–28. https://doi.org/10.1002/jnr.20432.Search in Google Scholar PubMed

31. Zanin, JP, Montroull, LE, Volosin, M, Friedman, WJ. The p75 neurotrophin receptor facilitates TrkB signaling and function in rat hippocampal neurons. Front Cell Neurosci 2019;13:1–11. https://doi.org/10.3389/fncel.2019.00485.Search in Google Scholar

32. Braak, H, Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239–59. https://doi.org/10.1007/bf00308809.Search in Google Scholar

33. Webster, MJ, Weickert, CS, Herman, MM, Kleinman, JE. BDNF mRNA expression during postnatal development, maturation and aging of the human prefrontal cortex. Dev Brain Res 2002;139:139–50. https://doi.org/10.1016/s0165-3806(02)00540-0.Search in Google Scholar

34. Hock, C, Heese, K, Hulette, C, Rosenberg, C, Otten, U. Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 2000;57:846–51. https://doi.org/10.1001/archneur.57.6.846.Search in Google Scholar PubMed

35. Peng, S, Wuu, J, Mufson, EJ, Fahnestock, M. Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 2005;93:1412–21. https://doi.org/10.1111/j.1471-4159.2005.03135.x.Search in Google Scholar PubMed

36. Buchman, AS, Yu, L, Boyle, PA, Schneider, JA, de Jager, PL, Bennett, DA. Higher brain BDNF gene expression is associated with slower cognitive decline in older adults. Neurology 2016;86:735–41. https://doi.org/10.1212/WNL.0000000000002387.Search in Google Scholar PubMed PubMed Central

37. Skilleter, AJ, Weickert, CS, Vercammen, A, Lenroot, R, Weickert, TW. Peripheral BDNF: a candidate biomarker of healthy neural activity during learning is disrupted in schizophrenia. Psychol Med 2015;45:841–54. https://doi.org/10.1017/S0033291714001925.Search in Google Scholar PubMed PubMed Central

38. Karege, F, Bondolfi, G, Gervasoni, N, Schwald, M, Aubry, JM, Bertschy, G. Low Brain-Derived Neurotrophic Factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatr 2005;57:1068–72. https://doi.org/10.1016/j.biopsych.2005.01.008.Search in Google Scholar PubMed

39. Nettiksimmons, J, Simonsick, EM, Harris, T, Satterfield, S, Rosano, C, Yaffe, K. The associations between serum brain-derived neurotrophic factor, potential confounders, and cognitive decline: a longitudinal study. PLoS ONE 2014;9. https://doi.org/10.1371/journal.pone.0091339.Search in Google Scholar PubMed PubMed Central

40. Cho, SY, Roh, HT. Effects of aerobic exercise training on peripheral brain-derived neurotrophic factor and eotaxin-1 levels in obese young men. J Phys Ther Sci 2016;28:1355–8. https://doi.org/10.1589/jpts.28.1355.Search in Google Scholar PubMed PubMed Central

41. Grosshans, DR, Clayton, DA, Coultrap, SJ, Browning, MD. LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1. Nat Neurosci 2002;5:27–33. https://doi.org/10.1038/nn779.Search in Google Scholar

42. Gruart, A, Muñoz, MD, Delgado-García, JM. Involvement of the CA3–CA1 synapse in the acquisition of associative learning in behaving mice. J Neurosci 2006;26:1077–87. https://doi.org/10.1523/JNEUROSCI.2834-05.2006.Search in Google Scholar

43. Patterson, SL, Grover, LM, Schwartzkroin, PA, Bothwell, M. Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 1992;9:1081–8. https://doi.org/10.1016/0896-6273(92)90067-n.Search in Google Scholar

44. Korte, M, Carroll, P, Wolf, E, Brem, G, Thoenen, H, Bonhoeffer, T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA 1995;92:8856–60. https://doi.org/10.1073/pnas.92.19.8856.Search in Google Scholar

45. Akaneya, Y, Tsumoto, T, Kinoshita, S, Hatanaka, H. Brain-derived neurotrophic factor enhances long-term potentiation in rat visual cortex. J Neurosci 1997;17:6707–16. https://doi.org/10.1523/jneurosci.17-17-06707.1997.Search in Google Scholar

46. Messaoudi, E, Ying, SW, Kanhema, T, Croll, SD, Bramham, CR. Brain-derived neurotrophic factor triggers transcription-dependent, late phase long-term potentiation in vivo. J Neurosci 2002;22:7453–61. https://doi.org/10.1523/jneurosci.22-17-07453.2002.Search in Google Scholar

47. Huber, KM, Sawtell, NB, Bear, MF. Brain-derived neurotrophic factor alters the synaptic modification threshold in visual cortex. Neuropharmacology 1998;37:571–9. https://doi.org/10.1016/s0028-3908(98)00050-1.Search in Google Scholar

48. Prieto, GA, Tong, L, Smith, ED, Cotman, CW. TNFα and IL-1β but not IL-18 suppresses hippocampal long-term potentiation directly at the synapse. Neurochem Res 2019;44:49–60. https://doi.org/10.1007/s11064-018-2517-8.Search in Google Scholar PubMed PubMed Central

49. Wang, XM, Pan, W, Xu, N, Zhou, ZQ, Zhang, GF, Shen, JC. Environmental enrichment improves long-term memory impairment and aberrant synaptic plasticity by BDNF/TrkB signaling in nerve-injured mice. Neurosci Lett 2019;694:93–8. https://doi.org/10.1016/j.neulet.2018.11.049.Search in Google Scholar PubMed

50. Citri, A, Malenka, RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 2008;33:18–41. https://doi.org/10.1038/sj.npp.1301559.Search in Google Scholar PubMed

51. Bliss, TVP, Collingridge, GL. A synaptic model of memory: Long-term potentiation in the hippocampus. Nature 1993;361:31–9. https://doi.org/10.1038/361031a0.Search in Google Scholar

52. Gordon-Weeks, PR, Fournier, AE. Neuronal cytoskeleton in synaptic plasticity and regeneration. J Neurochem 2014;129:206–12. https://doi.org/10.1111/jnc.12502.Search in Google Scholar

53. Kang, H, Jia, LZ, Suh, KY, Tang, L, Schuman, EM. Determinants of BDNF-induced hippocampal synaptic plasticity: role of the Trk B receptor and the kinetics of neurotrophin delivery. Learn Mem 1996;3:188–96. https://doi.org/10.1101/lm.3.2-3.188.Search in Google Scholar

54. Kellner, Y, Gödecke, N, Dierkes, T, Thieme, N, Zagrebelsky, M, Korte, M. The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity. Front Synaptic Neurosci 2014;6:185–99. https://doi.org/10.3389/fnsyn.2014.00005.Search in Google Scholar

55. Ji, Y, Lu, Y, Yang, F, Shen, W, Tang, TTT, Feng, L, et al.. Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 2010;13:302–9. https://doi.org/10.1038/nn.2505.Search in Google Scholar

56. Zagrebelsky, M, Gödecke, N, Remus, A, Korte, M. Cell type-specific effects of BDNF in modulating dendritic architecture of hippocampal neurons. Brain Struct Funct 2018;223:3689–709. https://doi.org/10.1007/s00429-018-1715-0.Search in Google Scholar

57. Zagrebelsky, M, Holz, A, Dechant, G, Barde, YA, Bonhoeffer, T, Korte, M. The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J Neurosci 2005;25:9989–99. https://doi.org/10.1523/JNEUROSCI.2492-05.2005.Search in Google Scholar

58. Cheung, ZH, Chin, WH, Chen, Y, Ng, YP, Ip, NY. Cdk5 is involved in BDNF-stimulated dendritic growth in hippocampal neurons. PLoS Biol 2007;5:e63. https://doi.org/10.1371/journal.pbio.0050063.Search in Google Scholar

59. Huang, YZ, Pan, E, Xiong, ZQ, McNamara, JO. Zinc-mediated transactivation of TrkB potentiates the hippocampal mossy fiber-CA3 pyramid synapse. Neuron 2008;57:546–58. https://doi.org/10.1016/j.neuron.2007.11.026.Search in Google Scholar

60. Toyomoto, M, Ohta, M, Okumura, K, Yano, H, Matsumoto, K, Inoue, S, et al.. Prostaglandins are powerful inducers of NGF and BDNF production in mouse astrocyte cultures. FEBS Letters 2004;562:211–5. https://doi.org/10.1016/S0014-5793(04)00246-7.Search in Google Scholar

61. Hirata, Y, Furuta, K, Suzuki, M, Oh-Hashi, K, Ueno, Y, Kiuchi, K. Neuroprotective cyclopentenone prostaglandins up-regulate neurotrophic factors in C6 glioma cells. Brain Res 2012;1482:91–100. https://doi.org/10.1016/j.brainres.2012.09.008.Search in Google Scholar PubMed

62. Cruz Duarte, P, St-Jacques, B, Ma, W. Prostaglandin E2 contributes to the synthesis of brain-derived neurotrophic factor in primary sensory neuron in ganglion explant cultures and in a neuropathic pain model. Exp Neurol 2012;234:466–81. https://doi.org/10.1016/j.expneurol.2012.01.021.Search in Google Scholar PubMed

63. Anglada-Huguet, M, Vidal-Sancho, L, Giralt, A, García-Díaz Barriga, G, Xifró, X, Alberch, J. Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington’s disease by the induction of BDNF-dependent synaptic plasticity. Neurobiol Dis 2016;95:22–34. https://doi.org/10.1016/j.nbd.2015.09.001.Search in Google Scholar PubMed

64. Yamada, N, Katsuura, G, Tatsuno, I, Kawahara, S, Ebihara, K, Saito, Y, et al.. Orexins increase mRNA expressions of neurotrophin-3 in rat primary cortical neuron cultures. Neurosci Lett 2009;450:132–5. https://doi.org/10.1016/j.neulet.2008.11.028.Search in Google Scholar PubMed

65. Liu, MF, Xue, Y, Liu, C, Liu, YH, Diao, HL, Wang, Y, et al.. Orexin – a exerts neuroprotective effects via OX1R in Parkinson’s disease. Front Neurosci 2018;12:302–9. https://doi.org/10.3389/fnins.2018.00835.Search in Google Scholar PubMed PubMed Central

66. Cohen, S, Matar, MA, Vainer, E, Zohar, J, Kaplan, Z, Cohen, H. Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder. Transl Psychiatry 2020;10. https://doi.org/10.1038/s41398-020-0698-9.Search in Google Scholar PubMed PubMed Central

67. Nylander, E, Zelleroth, S, Stam, F, Nyberg, F, Grönbladh, A, Hallberg, M. Growth hormone increases dendritic spine density in primary hippocampal cell cultures. Growth Horm IGF Res 2020;50:42–7. https://doi.org/10.1016/j.ghir.2019.12.003.Search in Google Scholar PubMed

68. Martinez-Moreno, CG, Fleming, T, Carranza, M, Ávila-Mendoza, J, Luna, M, Harvey, S, et al.. Growth hormone protects against kainate excitotoxicity and induces BDNF and NT3 expression in chicken neuroretinal cells. Exp Eye Res 2018;166. https://doi.org/10.1016/j.exer.2017.10.005.Search in Google Scholar PubMed

69. Mattson, MP, Maudsley, S, Martin, B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 2004;27:589–94. https://doi.org/10.1016/j.tins.2004.08.001.Search in Google Scholar PubMed

70. Buhot, MC, Martin, S, Segu, L. Role of serotonin in memory impairment. Ann Med 2000;32:210–21. https://doi.org/10.3109/07853890008998828.Search in Google Scholar PubMed

71. Cigliano, L, Spagnuolo, MS, Boscaino, F, Ferrandino, I, Monaco, A, Capriello, T, et al.. Dietary supplementation with fish oil or conjugated linoleic acid relieves depression markers in mice by modulation of the Nrf2 pathway. Mol Nutr Food Res 2019;63. https://doi.org/10.1002/mnfr.201900243.Search in Google Scholar PubMed

72. Lorinczova, HT, Fitzsimons, O, Mursaleen, L, Renshaw, D, Begum, G, Zariwala, MG. Co-administration of iron and a bioavailable curcumin supplement increases serum bdnf levels in healthy adults. Antioxidants 2020;9. https://doi.org/10.3390/antiox9080645.Search in Google Scholar PubMed PubMed Central

73. Abiri, B, Vafa, M. Effects of vitamin D and/or magnesium supplementation on mood, serum levels of BDNF, inflammatory biomarkers, and SIRT1 in obese women: a study protocol for a double-blind, randomized, placebo-controlled trial. Trials 2020;21. https://doi.org/10.1186/s13063-020-4122-9.Search in Google Scholar PubMed PubMed Central

74. Moghadas, M, Edalatmanesh, MA. Protective effect of Lithium Chloride against Trimethyltin-induced hippocampal degeneration and comorbid depression in rats. Comp Clin Pathol 2015;24:1165–75. https://doi.org/10.1007/s00580-014-2055-y.Search in Google Scholar

75. De-Paula, VJ, Gattaz, WF, Forlenza, O. Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations. Bipolar Disord 2016;18:692–5. https://doi.org/10.1111/bdi.12449.Search in Google Scholar PubMed

76. Bannova, Av., Menshanov, PN, Dygalo, NN. The effect of lithium chloride on the levels of brain-derived neurotrophic factor in the neonatal brain. Neurochem J 2019;13:344–8. https://doi.org/10.1134/s1819712419030048.Search in Google Scholar

77. Imamura, L, Yasuda, M, Kuramitsu, K, Hara, D, Tabuchi, A, Tsuda, M. Deltamethrin, a pyrethroid insecticide, is a potent inducer for the activity-dependent gene expression of brain-derived neurotrophic factor in neurons. J Pharmacol Exp Therapeut 2006;316:136–43. https://doi.org/10.1124/jpet.105.092478.Search in Google Scholar PubMed

78. Ihara, D, Fukuchi, M, Honma, D, Takasaki, I, Ishikawa, M, Tabuchi, A, et al.. Deltamethrin, a type II pyrethroid insecticide, has neurotrophic effects on neurons with continuous activation of the Bdnf promoter. Neuropharmacology 2012;62:1091–8. https://doi.org/10.1016/j.neuropharm.2011.10.023.Search in Google Scholar PubMed

79. Takasaki, I, Oose, K, Otaki, Y, Ihara, D, Fukuchi, M, Tabuchi, A, et al.. Type II pyrethroid deltamethrin produces antidepressant-like effects in mice. Behav Brain Res 2013;257:182–8. https://doi.org/10.1016/j.bbr.2013.09.044.Search in Google Scholar PubMed

80. Jämsä, A, Hasslund, K, Cowburn, RF, Bäckström, A, Vasänge, M. The retinoic acid and brain-derived neurotrophic factor differentiated SH-SY5Y cell line as a model for Alzheimer’s disease-like tau phosphorylation. Biochem Biophys Res Commun 2004;319:993–1000. https://doi.org/10.1016/j.bbrc.2004.05.075.Search in Google Scholar PubMed

81. Fukuchi, M. Identifying inducers of BDNF gene expression from pharmacologically validated compounds; antipyretic drug dipyrone increases BDNF mRNA in neurons. Biochem Biophys Res Commun 2020;524:957–62. https://doi.org/10.1016/j.bbrc.2020.02.019.Search in Google Scholar PubMed

82. Fereidooni, F, Komeili, G, Fanaei, H, Safari, T, Khorrami, S, Feizabad, AK. ☆Protective effects of ginseng on memory and learning and prevention of hippocampal oxidative damage in streptozotocin-induced Alzheimer’s in a rat model. Neurol Psychiatr Brain Res 2020;37:116–22. https://doi.org/10.1016/j.npbr.2020.08.001.Search in Google Scholar

83. Wang, G, Lei, C, Tian, Y, Wang, Y, Zhang, L, Zhang, R. Rb1, the primary active ingredient in Panax ginseng C.A. Meyer, exerts antidepressant-like effects via the BDNF–TrkB–CREB pathway. Front Pharmacol 2019;10:1034. https://doi.org/10.3389/fphar.2019.01034.Search in Google Scholar PubMed PubMed Central

84. Neshatdoust, S, Saunders, C, Castle, SM, Vauzour, D, Williams, C, Butler, L, et al.. High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: two randomised, controlled trials. Nutr Healthy Aging 2016;4:81–93. https://doi.org/10.3233/NHA-1615.Search in Google Scholar PubMed PubMed Central

85. Rendeiro, C, Vauzour, D, Rattray, M, Waffo-Téguo, P, Mérillon, JM, Butler, LT, et al.. Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLoS ONE 2013;8:e63535. https://doi.org/10.1371/journal.pone.0063535.Search in Google Scholar PubMed PubMed Central

86. Rezai, M, Mahmoodi, M, Kaeidi, A, Karimabad, MN, Khoshdel, A, Hajizadeh, MR. Effect of crocin carotenoid on BDNF and CREB gene expression in brain ventral tegmental area of morphine treated rats. Asian Pac J Trop Biomed 2018;8:387–93.10.4103/2221-1691.239426Search in Google Scholar

87. Stringham, NT, Holmes, P, Stringham, JM. Lutein supplementation increases serum brain-derived neurotrophic factor (BDNF) in humans. The FASEB J 2016;30.Search in Google Scholar

88. Hou, Y, Xie, G, Liu, X, Li, G, Jia, C, Xu, J, et al.. Minocycline protects against lipopolysaccharide-induced cognitive impairment in mice. Psychopharmacology 2016;233:905–16. https://doi.org/10.1007/s00213-015-4169-6.Search in Google Scholar PubMed

89. Portbury, SD, Hare, DJ, Finkelstein, DI, Adlard, PA. Trehalose improves traumatic brain injury-induced cognitive impairment. PLoS ONE 2017;12:e0183683. https://doi.org/10.1371/journal.pone.0183683.Search in Google Scholar PubMed PubMed Central

90. Liu, C, Chan, CB, Ye, K. 7,8-Dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders. Transl Neurodegener 2016;5. https://doi.org/10.1186/s40035-015-0048-7.Search in Google Scholar PubMed PubMed Central

91. Orr, ME, Sullivan, AC, Frost, B. A brief overview of tauopathy: causes, consequences, and therapeutic strategies. Trends Pharmacol Sci 2017;38:637–48. https://doi.org/10.1016/j.tips.2017.03.011.Search in Google Scholar PubMed PubMed Central

92. Hooper, C, Killick, R, Lovestone, S. The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 2008;104:1433–9. https://doi.org/10.1111/j.1471-4159.2007.05194.x.Search in Google Scholar PubMed PubMed Central

93. Mai, L, Jope, RS, Li, X. BDNF-mediated signal transduction is modulated by GSK3β and mood stabilizing agents. J Neurochem 2002;82:75–83. https://doi.org/10.1046/j.1471-4159.2002.00939.x.Search in Google Scholar PubMed

94. Bruna, B, Lobos, P, Herrera-Molina, R, Hidalgo, C, Paula-Lima, A, Adasme, T. The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca2+ signals, ERK and PI3K. Biochem Biophys Res Commun 2018;505:201–7. https://doi.org/10.1016/j.bbrc.2018.09.080.Search in Google Scholar PubMed

95. Neubrand, VE, Forte-Lago, I, Caro, M, Delgado, M. The atypical RhoGTPase RhoE/Rnd3 is a key molecule to acquire a neuroprotective phenotype in microglia. J Neuroinflammation 2018;15. https://doi.org/10.1186/s12974-018-1386-z.Search in Google Scholar PubMed PubMed Central

96. Jie, W, Andrade, KC, Lin, X, Yang, X, Yue, X, Chang, J. Pathophysiological functions of rnd3/RhoE. Compr Physiol 2016;6:169–86. https://doi.org/10.1002/cphy.c150018.Search in Google Scholar PubMed PubMed Central

Received: 2021-06-17
Accepted: 2021-10-11
Published Online: 2021-11-08

© 2021 Walter de Gruyter GmbH, Berlin/Boston