Disease relevance of BDNF

• Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling [1].
• Finally, in 15N neuroblastoma cells, which express BDNF mRNA but do not differentiate in response to RA, RA induced only a truncated form of TrkB [2].
• In postnatal intestine, BDNF immunoreactivity was primarily localized to enteric ganglion cells, with NT-3 localized to enteric plexuses, intermuscular basal lamina, and along or between circular and longitudinal smooth muscle cells [3].
• However, grafting of BDNF-producing fibroblasts two days before ischemia significantly and specifically prevented nerve cells from dying in the CA1 area of the ipsilateral hippocampus [4].
• BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated [5].

Psychiatry related information on BDNF

• BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease [6].
• Similar infusions of BDNF into the dorsal raphe nucleus produce an antidepressant effect, as evaluated by several 'learned helplessness' paradigms [7].
• Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems and interacts with the meso-limbic DA systems, involved in the therapeutic response to antipsychotic drugs and substance abuse [8].
• In the DVC, BDNF protein content decreased after 48 h food deprivation and increased after refeeding [9].
• Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations [10].

High impact information on BDNF

• We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein [11].
• These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF [11].
• , in this issue of Cell, integrate genetics and functional brain imaging by showing that variation in the human brain-derived neurotrophic factor (BDNF) gene is associated with variation in episodic memory ability and in hippocampal neurochemistry and function [12].
• NGF regulates the expression of a second neurotrophin, brain-derived neurotrophic factor (BDNF), in nociceptors [13].
• BDNF is released when nociceptors are activated, and it acts as a central modulator of pain [13].

Chemical compound and disease context of BDNF

• BDNF addition to RA-treated SH-SY5Y neuroblastoma cells stimulated the tyrosine phosphorylation of TrkB and neuronal differentiation [2].
• Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Eukaryotic Signal Transduction Group [2].
• This shows that MYCN overexpression per se is not sufficient to induce trkB expression. trkB expression and BDNF responsiveness in neuroblastoma cells can be induced by all-trans-retinoic acid (RA) [14].
• Significant differences in BDNF Val66Met genotype distribution were found between subjects dependent on methamphetamine (P = 0.046) or heroin (P = 0.045) and controls, suggesting that the lower 66Met carrier frequency is associated with substance abuse [15].
• To further elucidate the interaction between nicotine and BDNF, we examined the effect of nicotine on the proliferation of the neuroblastoma cell line SH-SY5Y, which, following differentiation with retinoic acid, expresses both nicotinic receptors and the receptor for BDNF, TrkB [16].

Biological context of BDNF

• Anterograde axonal transport provides an 'afferent supply' of BDNF and NT-3 to neurons and target tissues, where they function as trophic factors and as neurotransmitters [17].
• These results suggest the possibility that decreased expression of BDNF may contribute to the progression of cell death in AD [6].
• Addition of BDNF protects human MM cell lines (HMCLs) from apoptosis induced by dexamethasone or bortezomib and prolongs the survival of primary MM cells cultured alone or with human bone marrow (BM) stroma [18].
• In addition, BDNF appears to promote cell survival and neurite outgrowth [19].
• During the last decade, evidence has accumulated implicating them (especially BDNF) in addition in the regulation of synaptic transmission and synaptogenesis in the CNS [20].

Anatomical context of BDNF

• Activated TrkA receptor levels and the survival of NGF-dependent sensory neurons, but not BDNF-dependent sensory neurons, are directly influenced by Nedd4-2 expression [21].
• Together, these findings suggest that BDNF may be released from primary sensory nociceptors with activity, particularly in some persistent pain states, and may then increase the excitability of rostrally projecting second-order systems [22].
• Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner [19].
• Finally, BDNF is expressed by malignant plasma cells isolated from a subset of patients with MM, as well as by most HMCLs, suggesting a potential role for this neurotrophin axis in autocrine as well as paracrine support of MM [18].
• Thus, our results show that BDNF is able to up-regulate the expression of TrkB in control and pathological states, and that BDNF prevention of neuronal death following transient forebrain ischemia is associated with increased expression of its specific receptor [4].

Associations of BDNF with chemical compounds

• Exogenous BDNF induces tyrosine phosphorylation of TRK-B as well as phosphorylation of phospholipase C-gamma 1, the extracellular signal-regulated kinases 1 and 2, and phosphatidylinositol-3 kinase [19].
• BDNF also protected TrkB-expressing NGP and KCNR NB cells from chemotherapeutic agent-induced cell death, and LY294002 inhibited this protection [23].
• BDNF treatment of high TrkB-expressing TB8 (Tet-) and TB3 (Tet-) cells blocked drug-induced cell death in a dose-dependent manner [23].
• This domain was cross-linked to BDNF through a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide coupling reaction [24].
• BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically) [25].

Physical interactions of BDNF

• These results, obtained from a variety of experimental techniques, highlight the importance of two distinct regions of the extracellular domain of the TRKB receptor in binding BDNF [24].
• Results obtained with cells transfected with the low-affinity NGF receptor gene indicate that these cells bind BDNF, in addition to NGF, whereas cells before transfection do not [26].
• Sections dual immunoreacted for BNNF and tyrosine hydroxylase revealed a subpopulation of dopaminergic neurons (approximately 28%) within the pars compacta which contained retrogradely transported BDNF [27].
• In MPTP-treated marmosets BDNF caused increased ipsilateral striatal [3H]mazindol binding with increased somatic size and staining intensity in GAD-immunoreactive cells and a 10-20% loss of nigral TH-immunoreactive cells with increased GFAP staining [28].
• When NGF binding to p75NTR was blocked by treating cells with either BDNF or PD90780, and where p75NTR expression was reduced by treating cells with antisense oligonucleotide to p75NTR, the protective effects of NGF were attenuated [29].

Regulatory relationships of BDNF

• In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression [8].
• BDNF induces phosphorylation of FRS2 [30].
• In addition, we show that RA and BDNF regulate N-linked glycosylation of APLP1 [31].
• However, the signaling properties of I98V, P660L and T821A were all indistinguishable from wild type.Conclusion:We provide further evidence for the impairment in signaling by Y722C and show that as well as a loss of signaling, this mutation affects the ability of TrkB to promote neurite outgrowth in response to BDNF [32].
• The phenotypic differentiation of locus ceruleus noradrenergic neurons mediated by brain-derived neurotrophic factor is enhanced by corticotropin releasing factor through the activation of a cAMP-dependent signaling pathway [33].

Other interactions of BDNF

• Here, we provide evidence that the TrkB-BDNF pathway is associated with enhanced survival and resistance to chemotherapy in neuroblastoma [34].
• VEGF mRNA levels in neuroblastoma cells cultured in serum-free media increased after 8 to 16 hours in BDNF [5].
• Comparison of the biophysical characteristics of human brain-derived neurotrophic factor, neurotrophin-3, and nerve growth factor [35].
• Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD [25].
• Expression of CAMKII-alpha and TBR1 mRNAs was significantly increased in bipolar patients but not in major depressed patients, and there was a trend toward reduced BDNF expression in both groups [36].

Analytical, diagnostic and therapeutic context of BDNF

• Environmental stressors such as immobilization induce depression and decrease BDNF mRNA [7].
• Spinal neurons show increased excitability to nociceptive inputs after treatment with exogenous BDNF [22].
• Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall [37].
• Furthermore, when the TrkB tyrosine kinase was blocked with the Trk-specific inhibitor CEP-2563, or by neutralizing antibody to BDNF, sensitivity to chemotherapy was significantly increased [34].
• Metabolic labeling, immunoprecipitation, and SDS-polyacrylamide gel electrophoresis reveal that pro-BDNF is generated as a 32-kDa precursor that is N-glycosylated and glycosulfated on a site, within the pro-domain [38].

References