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
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.
Available from: Xiang Yang Zhang
- "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.
- "Furthermore, no studies (to date) have investigated histone acetylation at bdnf or reelin regulatory regions after exposure to maltreatment in infancy. Because bdnf and reelin code for proteins important in neural development and plasticity, these genes are widely implicated in various psychiatric disorders (Abdolmaleky et al., 2005; Boulle et al., 2012; Martinowich et al., 2007; Nagahara & Tuszynski, 2011; Tissir & Goffinet, 2003). BDNF is released from dendrites, axons and terminals in an activity-dependent manner to modulate synaptic strength and neuronal connectivity (Balkowiec & Katz, 2002; Martinowich et al., 2007). "
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ABSTRACT: Infant–caregiver experiences are major contributing factors to neural and behavioral development. Research indicates that epigenetic mechanisms provide a way in which infant–caregiver experiences affect gene activity and other downstream processes in the brain that influence behavioral development. Our laboratory previously demonstrated in a rodent model that exposure to maltreatment alters methylation of DNA associated with the brain-derived neurotrophic factor (bdnf) and reelin genes as well as mRNA of key epigenetic regulatory genes in the medial prefrontal cortex (mPFC). In the current study, we characterized patterns of histone acetylation at bdnf and reelin gene loci after our caregiver manipulations. Using a within-litter design (n = 8–10/group from eight litters), pups were exposed to adverse (maltreatment condition: exposure to a stressed caregiver) or nurturing (cross-foster condition: exposure to a nurturing caregiver) caregiving environments outside the home cage for 30 min daily during the first postnatal week. Remaining pups in a litter were left with the biological mother during each session (providing normal care controls). We then used chromatin immunoprecipitation (ChIP) and quantitative RT-PCR to measure histone 3 lysine 9/14 acetylation associated with bdnf promoters I and IV and the reelin promoter in the adult mPFC. Maltreated females had decreased acetylation at bdnf IV, while neither males nor females exhibited histone acetylation alterations at bdnf I or reelin. These data demonstrate the ability of maltreatment to have long-term consequences on histone acetylation in the mPFC, and provide further evidence of the epigenetic susceptibility of bdnf IV to the quality of infant–caregiver experiences.
Available from: M. Foster Olive
- "The DNA methylation status and expression levels of BDNF in the prefrontal cortex were rescued by chronic intracerebroventricular treatment with a DNMT inhibitor. BDNF has emerged as having somewhat of a ubiquitous role in brain functioning, and is implicated in various diseases, including depression, stroke, Alzheimer's, and addictive disorders (Nagahara and Tuszynski, 2011; Biliński et al., 2012). Thus, evidence that ELS can trigger BDNF expression changes in adulthood has immense implications concerning vulnerability toward the development of these disorders. "
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ABSTRACT: Early life stress interacts with adult stress to differentially modulate neural systems and vulnerability to various psychiatric illnesses. However, the effects of early life stress and adult stress on addictive behaviors have not been sufficiently investigated. We examined the effects of early life stress in the form of prolonged maternal separation, followed in early adulthood by either 10 days of chronic variable stress or no stress, on methamphetamine self-administration, extinction, and cue-induced reinstatement. We observed that chronic variable stress in adulthood reduced methamphetamine self-administration in rats with a history of early life stress. These findings add to an emerging body of literature suggesting interactions between early life and early adulthood stressors on adult behavioral phenotypes.
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