Potential therapeutic uses of BDNF in neurological and psychiatric disorders.

Center for Neural Repair, Department of Neurosciences 0626, University of California, San Diego, La Jolla, California 92093, USA.
dressNature Reviews Drug Discovery (Impact Factor: 37.23). 03/2011; 10(3):209-19. DOI: 10.1038/nrd3366
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Third trimester-equivalent alcohol exposure causes significant deficits in hippocampal and cortical neuroplasticity, resulting in alterations to dendritic arborization, hippocampal adult neurogenesis, and performance on learning tasks. The current study investigated the impact of neonatal alcohol exposure (postnatal days 4-9, 5.25g/kg/day) on expression of brain-derived neurotrophic factor (BDNF) and the tropomyosin-related kinase B (TrkB) receptor in the hippocampal and frontal cortex of infant Long-Evans rats. Levels of BDNF protein were increased in the hippocampus, but not frontal cortex, of alcohol-exposed rats 24hrs after the last dose, when compared with undisturbed (but not sham-intubated) control animals. BDNF protein levels showed a trend towards increase in hippocampus of sham-intubated animals as well, suggesting an effect of the intubation procedure. TrkB protein was increased in the hippocampus of alcohol-exposed animals compared to sham-intubated pups, indicating an alcohol-specific effect on receptor expression. In addition, expression of bdnf total mRNA in alcohol-exposed and sham-intubated pups was enhanced in the hippocampus; however, there was a differential effect of alcohol and intubation stress on exon I- and IV-specific mRNA transcripts. Further, plasma corticosterone was found to be increased in both alcohol-exposed and sham-intubated pups compared to undisturbed animals. Upregulation of BDNF could potentially represent a neuroprotective mechanism activated following alcohol exposure or stress. The results suggest that alcohol exposure and stress have both overlapping and unique effects on BDNF, and highlight the need for the stress of intubation to be taken into consideration in studies that implement this route of drug delivery. Copyright © 2015. Published by Elsevier Ltd.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 03/2015; 43. DOI:10.1016/j.ijdevneu.2015.03.008 · 2.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic function and plasticity and plays important roles in neuronal development, survival, and brain disorders. Despite such diverse and important roles, how BDNF, or more generally speaking, neurotrophins affect synapses, particularly nerve terminals, remains unclear. By measuring calcium currents and membrane capacitance during depolarization at a large mammalian central nerve terminal, the rat calyx of Held, we report for the first time that BDNF slows down calcium channel activation, including P/Q-type channels, and inhibits exocytosis induced by brief depolarization or single action potentials, inhibits slow and rapid endocytosis, and inhibits vesicle mobilization to the readily releasable pool. These presynaptic mechanisms may contribute to the important roles of BDNF in regulating synapses and neuronal circuits and suggest that regulation of presynaptic calcium channels, exocytosis, and endocytosis are potential mechanisms by which neurotrophins achieve diverse neuronal functions. Copyright © 2015 the authors 0270-6474/15/354676-07$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2015; 35(11):4676-82. DOI:10.1523/JNEUROSCI.2695-14.2015 · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 5.20 Impact Factor