Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment
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Depression and posttraumatic stress disorder are assumed to be maladaptive responses to stress and antidepressants are thought to counteract such responses by increasing BDNF (brain-derived neurotrophic factor) levels. BDNF acts through TrkB (tropomyosin-related receptor kinase B) and plays a central role in neuroplasticity. In contrast, both precursor proBDNF and BDNF propeptide (another metabolic product from proBDNF cleavage) have a high affinity to p75 receptor (p75R) and usually convey apoptosis and neuronal shrinkage. Although BDNF and proBDNF/propeptide apparently act in opposite ways, neuronal turnover and remodeling might be a final common way that both act to promote more effective neuronal networking, avoiding neuronal redundancy and the misleading effects of environmental contingencies. This review aims to provide a brief overview about the BDNF functional role in antidepressant action and about p75R and TrkB signaling to introduce the "continuum-sorting hypothesis." The resulting hypothesis suggests that both BDNF/proBDNF and BDNF/propeptide act as protagonists to fine-tune antidepressant-dependent neuroplasticity in crucial brain structures to modulate behavioral responses to stress.
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BDNF has been consistently associated with the therapeutic effect of antidepressant drugs.
“BDNF has been consistently associated to the therapeutic effect of antidepressant drugs [199,200,201].”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [201]
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Sales, A. J., Fogaça, M. V., Sartim, A. G., Pereira, V. S., Wegener, G., Guimarães, F. S., & Joca, S. R. L. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1143-4 · Cited by 199 · see citing works
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Sarcopenia and Cognitive Decline in Older Adults: Targeting the Muscle–Brain Axis
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“Trk receptors are expressed by both motor neurons and skeletal myocytes, and their downstream signaling leads to the activation of PI3K, mitogen-activated protein kinase (MAPK), and phospholipase C-γ (PLCγ) pathways [89], ultimately supporting neuronal survival [91].”
BackgroundP2X7 Receptor Signaling in Stress and Depression
Ribeiro, D. E., Roncalho, A. L., Glaser, T., Ulrich, H., Wegener, G., & Joca, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112778 · Cited by 129 · see citing works
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Changes in Hippocampal Plasticity in Depression and Therapeutic Approaches Influencing These Changes
Xu, W., Yao, X., Zhao, F., Zhao, H., Cheng, Z., Yang, W., Cui, R., Xu, S., & Li, B. (2020) · Neural Plasticity · doi:10.1155/2020/8861903 · Cited by 73 · see citing works
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Szarowicz, C., Steece‐Collier, K., & Caulfield, M. E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23148011 · Cited by 41 · see citing works
“regulation of cellular proliferation [18,45,53,56].”
BackgroundInfluentialSerotonin Receptor 5-HT2A Regulates TrkB Receptor Function in Heteroreceptor Complexes
Ilchibaeva, T. V., Tsybko, A. S., Zeug, A., Müller, F. E., Guseva, D., Bischoff, S. C., Ponimaskin, E. G., & Naumenko, V. S. (2022) · Cells · doi:10.3390/cells11152384 · Cited by 37 · see citing works
The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice
Tsybko, A. S., Ilchibaeva, T. V., Filimonova, E., Eremin, D. V., Popova, N. K., & Naumenko, V. S. (2020) · Neurochemical Research · doi:10.1007/s11064-020-03153-5 · Cited by 29 · see citing works
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Kapoor, T., & Mehan, S. (2020) · Current Drug Discovery Technologies · doi:10.2174/1570163817666200207100903 · Cited by 26 · see citing works
Sun, W., Che, H., Li, J., Tang, D., Liu, X., Liu, W., & An, L. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02051-9 · Cited by 24 · see citing works
Gao, R., Ren, L., Zhou, Y., Wang, L., Xie, Y., Zhang, M., Liu, X., Ke, S., Wu, K., Zheng, J., et al. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111192 · Cited by 25 · see citing works
DNA methylation in stress and depression: from biomarker to therapeutics
Sales, A. J., Guimarães, F. S., & Joca, S. R. L. (2021) · Acta Neuropsychiatrica · doi:10.1017/neu.2021.18 · Cited by 27 · see citing works
Norgren, J., Daniilidou, M., Kåreholt, I., Sindi, S., Akenine, U., Nordin, K., Rosenborg, S., Ngandu, T., Kivipelto, M., & Matton, A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.716594 · Cited by 23 · see citing works
“The brain is dependent on a balance between these counteracting mechanisms in order to fine-tune neurological networks and maintain plasticity (Lu et al., 2005; Diniz et al., 2018).”
BackgroundDuarte-Silva, E. P., Oriá, A. C., Mendonça, I. P., de Melo, M. G., de Paiva, I. H. R., Maes, M. H. J., Joca, S. R. L., & Peixoto, C. A. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104582 · Cited by 21 · see citing works
ProBDNF signaling is involved in periodontitis-induced depression-like behavior in mouse hippocampus
Li, Y., Guan, X., He, Y., Jia, X., Pan, L., Wang, Y., Han, Y., Zhao, R., Yang, J., & Hou, T. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109767 · Cited by 24 · see citing works
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Zhao, J., Jia, H., Ma, P., Zhu, D. Y., & Fang, Y. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107717 · Cited by 19 · see citing works
Diniz, C. R. A. F., Crestani, A. P., Casarotto, P. C., Biojone, C., Cannarozzo, C., Winkel, F., Prozorov, M. A., Kot, E. F., Goncharuk, S. A., Marques, D. B., et al. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.06.021 · Cited by 16 · see citing works
Stress modulates Ahi1-dependent nuclear localization of ten-eleven translocation protein 2
Zhang, Q., Hu, Q., Wang, J., Miao, Z., Li, Z., Zhao, Y., Wan, B., Allen, E. G., Sun, M., Jin, P., et al. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab179 · Cited by 16 · see citing works
Wu, G. W. Y., Wolkowitz, O. M., Reus, V. I., Kang, J. I., Elnar, M., Sarwal, R. D., Flory, J. D., Amara, D. A., Hammamieh, R., Gautam, A., et al. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105360 · Cited by 15 · see citing works
“Alternatively, increased BDNF in PTSD could be a pathophysiological mechanism itself, due to the over-consolidation of traumatic memories around the time of the trauma (Diniz et al., 2018; Matsuoka et al., 2013).”
BackgroundLuo, R., Luo, C., Zhong, F., Shen, W., Li, H., Zhang, Y., & Dai, R. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02113-y · Cited by 12 · see citing works
Guo, J., Yang, Y., Jiang, X., Guo, M., Li, X., Huang, P. H., & Liu, Z. (2020) · Gene · doi:10.1016/j.gene.2020.145192 · Cited by 12 · see citing works
Pettorruso, M., Miuli, A., Clemente, K., Mancusi, G., Migliara, G., Carlo, F. D., Pernaci, G., Crosta, T. D., Santorelli, M., d’Andrea, G., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02367-7 · Cited by 12 · see citing works
“Despite the assumption that proBDNF and BDNF have opposing roles [12], both are deemed essential for preserving functional homeostasis within the central nervous system.”
BackgroundLin, L., Zhou, X., & Bobrovskaya, L. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112905 · Cited by 11 · see citing works
Lima‐Ojeda, J. M., Rupprecht, R., & Baghai, T. C. (2020) · Der Nervenarzt · doi:10.1007/s00115-020-01029-1 · Cited by 11 · see citing works
Wei, Q., Li, M., Du, Q., Zhang, H., Liang, Y., Cheng, C., Mei, B., Yang, X., Fan, Y., Zhu, J., et al. (2025) · Journal of Clinical Anesthesia · doi:10.1016/j.jclinane.2025.111821 · Cited by 10 · see citing works
Diniz, C. R. A. F., da Silva, L. A., Domingos, L. B., Sonego, A. B., Moraes, L. R. B., & Joca, S. R. L. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110451 · Cited by 10 · see citing works
Sun, W., Mei, Y., Li, X., Yang, Y., & An, L. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1018586 · Cited by 9 · see citing works
“Anatomical and histological observation also found that the up-regulation of proBDNF/mBDNF ratio induced synaptic plasticity impairment, and cognitive decline in depressive episodes and aged (Diniz et al., 2018; Wang et al., 2021), indicating BDNF has bidirectional effects on neuronal function depending on the cleavag…”
BackgroundWan, X.-J., Xie, J.-L., Yang, M.-J., Yu, H., Hou, W.-K., Xu, K., Wang, J.-C., & Xu, P. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12041405 · Cited by 11 · see citing works
“At this stage, it is believed to be closely related to inflammation and cytokines [3,4], monoamine neurotransmitters and their receptors [5], neurotrophic factors [6,7], and the hypothalamic–pituitary–adrenal (HPA) endocrine axis [8].”
BackgroundHernández‐Hernández, E., Ledesma‐Corvi, S., Yáñez, F., Garau, C., Gálvez‐Melero, L., Bagán, A., Escolano, C., & García-Fuster, M. J. (2023) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2023.173527 · Cited by 9 · see citing works
“Finally, mBDNF was evaluated as a key molecular marker mediating antidepressant-like actions (e.g., Diniz et al., 2018; Casarotto et al., 2021), together with the regulation of hippocampal cell proliferation (e.g., Numakawa et al., 2018), since hippocampus is a key region modulating affect…”
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Fast-acting antidepressant-like effects of ketamine in aged male rats
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The researcher's guide to selecting biomarkers in mental health studies
Verhoeven, J. E., Wolkowitz, O. M., Satz, I. B., Conklin, Q. A., Lamers, F., Lavebratt, C., Lin, J., Lindqvist, D., Mayer, S. E., Melas, P. A., et al. (2024) · BioEssays · doi:10.1002/bies.202300246 · Cited by 9 · see citing works
“Some studies questioned the specificity of the current ELISA technique to differentiate mBDNF from pro-BDNF, [211] although circulating pro-BDNF levels are very low.”
ProBDNF as an Indicator of Improvement among Women with Depressive Episodes
Zwolińska, W., Skibińska, M., Słopień, A., & Dmitrzak‐Węglarz, M. (2022) · Metabolites · doi:10.3390/metabo12040358 · Cited by 8 · see citing works
“Stress is an environmental factor well-known for its notorious part in the development of psychiatric disorders, possibly through altering the expression of stress-related genes, such as BDNF [4,26].”
BackgroundGomez, J., Haas, N. A., & Schwarz, J. M. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05194-3 · Cited by 6 · see citing works
Involvement of proBDNF in Monocytes/Macrophages with Gastrointestinal Disorders in Depressive Mice
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Emerging and evolving concepts in the pathobiology and treatment of psychosis
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Early Alcohol Withdrawal Reverses the Abnormal Levels of proBDNF/mBDNF and their ReceptorsPreprint
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“Though mature BDNF (mBDNF) is generated from the cleavage of the precursor (proBDNF), they play different, even the opposite roles in neuronal survival, differentiation and plasticity [13-15].”
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“Because these isoforms are known to exert different effects on synaptic plasticity through distinct receptor systems 42 , it remains unclear which component of BDNF signaling contributes to the observed behavioral and molecular effects.”
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“The most frequent trajectory pairing was Stable Ascent mBDNF with a Gradual Increase in proBDNF, occurring in 70.3% of participants.”
InfluentialThe Role of P2X7 Receptors in the Pathogenesis of Depression and Autism Spectrum Disorders
(2025) · Molekulyarnaya Meditsina (Molecular medicine) · doi:10.29296/24999490-2025-04-10
Kalinina, T. S., Sukhareva, E. V., Lanshakov, D. A., Bulygina, V. V., & Дыгало, Н. Н. (2025) · Neurochemical Journal · doi:10.1134/s1819712425700436
- Authors
- Diniz, C. R. A. F., Casarotto, P. C., Resstel, L., & Joca, S. R. L.
- Affiliations
- Universidade de São Paulo (BR)
- University of Helsinki (FI)
- Corresponding author
- Diniz, Cassiano R.A.F.
- Venue
- Neuroscience & Biobehavioral Reviews
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 90
- Pages
- 70-83
- ISSN
- 0149-7634 (ISSN-L)
- OpenAlex
- W2795628695
- Semantic Scholar
- 901c33994c7064d67a1d28eaac7aa0969a073d89
- Cited by
- 58
- References
- 222
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 6 · 2023: 5 · 2022: 5 · 2021: 10 · 2020: 14 · 2019: 4 · 2018: 3
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Neuroscience & Biobehavioral Reviews (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- European Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- brain-derived neurotrophic factor, proBDNF, antidepressant action, depression, post-traumatic stress disorder, TrkB signaling, p75 neurotrophin receptor, neuroplasticity, neuronal turnover, neuronal remodeling, stress response
- MeSH terms
- Antidepressive Agents, Brain, Depression, Neuronal Plasticity, Neurons, Brain-Derived Neurotrophic Factor
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