Nagahara AH, Tuszynski MH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10: 209-219

Center for Neural Repair, Department of Neurosciences 0626, University of California, San Diego, La Jolla, California 92093, USA.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 03/2011; 10(3):209-19. DOI: 10.1038/nrd3366
Source: PubMed


The growth factor brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase receptor type B (TRKB) are actively produced and trafficked in multiple regions in the adult brain, where they influence neuronal activity, function and survival throughout life. The diverse presence and activity of BDNF suggests a potential role for this molecule in the pathogenesis and treatment of both neurological and psychiatric disorders. This article reviews the current understanding and future directions in BDNF-related research in the central nervous system, with an emphasis on the possible therapeutic application of BDNF in modifying fundamental processes underlying neural disease.

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    • "BDNF in the blood may reflect the level of BDNF in the brain. Together, these findings confirm that BDNF is involved in schizophrenia (Nagahara and Tuszynski, 2011). A further finding of our present study is the increased IL-2, IL-6, and IL-8 levels but decreased TNF-a levels in chronic schizophrenia patients. "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.
    Brain Behavior and Immunity 09/2015; DOI:10.1016/j.bbi.2015.09.014 · 5.89 Impact Factor
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    • "Our data showed that these two treatment groups exhibited no significant difference on stimulating TrkB phosphorylation 6 h following SAH, while the HIOC group showed improved neurobehavioral outcomes and exerted a tendency of activating TrkB more potently than the BDNF group 24 h post-SAH (Figs. 5, 6). It has been reported that BDNF has poor blood brain barrier penetrability and short serum half-life, and induces TrkB polyubiquitination and degradation, and these features made BDNF's clinical application problematic (Nagahara and Tuszynski, 2011; Shen et al., 2012). From this observation , it seems that HIOC, as a small compound, is more efficient and has prolonged effects on activating TrkB and its downstream effector than BDNF, thus a good candidate for future consideration. "
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    ABSTRACT: N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC), an N-acetyl serotonin's derivative, selectively activates tropomyosin-related kinase receptor B (TrkB). This study is to investigate a potential role of HIOC on ameliorating early brain injury after experimental subarachnoid hemorrhage (SAH). One hundred and fifty-six adult male Sprague-Dawley rats were used. SAH model was induced by endovascular perforation. TrkB small interfering RNA (siRNA) or scramble siRNA was injected intracerebroventricularly 24hours before SAH. HIOC was administrated intracerebroventricularly 3hours after SAH and compared with brain-derived neurotrophic factor (BDNF). SAH grade and neurologic scores were evaluated for the outcome study. For the mechanism study, the expression of TrkB, phosphorylated TrkB (p-TrkB), phosphorylated extracellular signal regulated kinase (p-ERK), B-cell lymphoma 2 (Bcl-2) and cleaved caspase 3 (CC3) were detected by Western blots, and neuronal injury was determined by double immunofluorescence staining of neuronal nuclei and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling. Knocking down of TrkB decreased the expression of Bcl-2 and aggravated neurologic deficits 24hours after SAH. HIOC activated TrkB/ERK pathway, decreased neuronal cell death, improved neurobehavioral outcome, and these effects were abolished by TrkB siRNA. HIOC was more potent than BDNF in reduction of apoptosis 24hours post-SAH. Thus, we conclude that administration of HIOC activated TrkB/ERK signaling cascade and attenuated early brain injury after SAH. HIOC may be a promising agent for further treatment for SAH and other stroke events. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 04/2015; 78. DOI:10.1016/j.nbd.2015.01.009 · 5.08 Impact Factor
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    • "Thus, lower levels of BDNF are consistent with the hypothesis that a deficit in this neurotrophic factor may contribute to the structural and functional alterations of brain X.Y. Zhang et al. underlying the psychopathology of schizophrenia (Nagahara and Tuszynski, 2011), supporting the hypothesis of a neurodegenerative process in schizophrenia. A further finding of our present study is decreased activities of SOD and GSH-Px and unchanged CAT in chronic patients with schizophrenia, which is in agreement with some recent studies finding a decrease of erythrocyte SOD and GSH-Px levels (Ranjekar et al., 2003; Zhang et al., 2006; Ben Othmen et al., 2008). "
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    ABSTRACT: Neurodegenerative processes may be involved in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF), the most widely distributed neurotrophin and oxidative stress (OS) may be critical for several pathological manifestations of neurodegenerative disorders. Accumulating evidence suggests that both BDNF and OS may be involved in the pathophysiology of schizophrenia. However, the possible interaction between BDNF and OS has been under-investigated. Serum BDNF, plasma malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were analyzed using established procedures in 164 chronic medicated schizophrenia and 50 healthy controls. Schizophrenic symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) with cognitive and depressive factors derived from the five factor model of the PANSS. Compared to the control group, the patients exhibited a significant decrease in BDNF levels, in the activities of SOD and GSH-Px but a significant increase in MDA levels. In patients, but not in controls, we observed a significant negative correlation between BDNF and SOD. Furthermore, the interaction between BDNF and CAT was associated with the PANSS cognitive factor, and the interaction between BDNF and GSH-Px with the PANSS depressive factor. Both decreased BDNF levels and OS may be implicated in the pathophysiology of chronic schizophrenia. Their inverse association only in the schizophrenia group may reflect a pathological mechanism involving an interaction of oxidative damage and neurotrophin dysfunction. Moreover, OS may interact with the BDNF system to influence the clinical symptoms and cognitive impairment in schizophrenia, which is line with the neurodevelopmental hypothesis of schizophrenia.
    Psychoneuroendocrinology 01/2015; 51. DOI:10.1016/j.psyneuen.2014.09.029 · 4.94 Impact Factor
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