Protective Effect Of Brain-derived Neurotrophic Factor Research Articles

TrkB-Mediated Neuroprotective and Antihypoxic Properties of Brain-Derived Neurotrophic Factor.

The neuroprotective and antihypoxic effects of brain-derived neurotrophic factor (BDNF) on dissociated hippocampal cultures in a hypoxia model were investigated. These experiments demonstrate that 10 minutes of normobaric hypoxia increased the number of dead cells in primary culture, whereas a preventive application of BDNF increased the number of viable cells. Spontaneous bioelectrical and calcium activity in neural networks was analyzed using multielectrode arrays and functional intravital calcium imaging. The results indicate that BDNF affects the functional parameters of neuronal networks in dissociated hippocampal cultures over the 7-day posthypoxic period. In addition, the effects of k252a, an antagonist of tropomyosin-related kinase B (TrkB), on functional bioelectrical activity during and after acute hypoxia were investigated. It was shown that the protective effects of BDNF are associated with binding to the TrkB receptor. Finally, intravital fluorescent mRNA probes were used to study the role of NF-κB1 in the protective effects of BDNF. Our experiments revealed that BDNF application stimulates NF-κB1 mRNA synthesis in primary dissociated hippocampal cells under normal conditions but not in hypoxic state.

Protective Effects of BDNF against C-Reactive Protein-Induced Inflammation in Women.

Background. Since high sensitivity C-reactive protein (hsCRP) is predictive of cardiovascular events, it is important to examine the relationship between hsCRP and other inflammatory and oxidative stress markers linked to cardiovascular disease (CVD) etiology. Previously, we reported that hsCRP induces the oxidative stress adduct 8-oxo-7,8-dihydro-2′deoxyguanosine (8-oxodG) and that these markers are significantly associated in women. Recent data indicates that brain-derived neurotrophic factor (BDNF) may have a role in CVD. Methods and Results. We examined BDNF levels in 3 groups of women that were age- and race-matched with low (<3 mg/L), mid (>3–20 mg/L), and high (>20 mg/L) hsCRP (n = 39 per group) and found a significant association between hsCRP, BDNF, and 8-oxodG. In African American females with high hsCRP, increases in BDNF were associated with decreased serum 8-oxodG. This was not the case in white women where high hsCRP was associated with high levels of BDNF and high levels of 8-oxodG. BDNF treatment of cells reduced CRP levels and inhibited CRP-induced DNA damage. Conclusion. We discovered an important relationship between hsCRP, 8-oxodG, and BDNF in women at hsCRP levels >3 mg/L. These data suggest that BDNF may have a protective role in counteracting the inflammatory effects of hsCRP.

Blocking GSK3β-mediated dynamin1 phosphorylation enhances BDNF-dependent TrkB endocytosis and the protective effects of BDNF in neuronal and mouse models of Alzheimer's disease

Endocytosis of tropomyosin related kinase B (TrkB) receptors has critical roles in brain-derived neurotrophic factor (BDNF) mediated signal transduction and biological function, however the mechanism that is governing TrkB endocytosis is still not completely understood. In this study, we showed that GSK3β, a key kinase in neuronal development and survival, could regulate TrkB endocytosis through phosphorylating dynamin1 (Dyn1) but not dynamin2 (Dyn2). Moreover, we found that beta-amyloid (Aβ) oligomer exposure could impair BDNF-dependent TrkB endocytosis and Akt activation through enhancing GSK3β activity in cultured hippocampal neurons, which suggested that BDNF-induced TrkB endocytosis and the subsequent signaling were impaired in neuronal model of Alzheimer's disease (AD). Notably, we found that inhibiting GSK3β phosphorylating Dyn1 by using TAT-Dyn1SpS could rescue the impaired TrkB endocytosis and Akt activation upon BDNF stimuli under Aβ exposure. Finally, TAT-Dyn1SpS could facilitate BDNF-mediated neuronal survival and cognitive enhancement in mouse models of AD. These results clarified a role of GSK3β in BDNF-dependent TrkB endocytosis and the subsequent signaling, and provided a potential new strategy by inhibiting GSK3β-induced Dyn1 phosphorylation for AD treatment.

Developmental changes in the protective effect of exogenous brain-derived neurotrophic factor and neurotrophin-3 against ototoxic drugs in cultured rat vestibular ganglion neurons

We examine developmental changes in the responsiveness of rat vestibular ganglion neurons (VGNs) to two neurotrophic factors (NTFs), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and investigate the protective effects of these NTFs against ototoxic drugs during postnatal development in dissociated cultures. VGNs were obtained from rats on postnatal days (P) 1, 3, 7 and 14. BDNF facilitated neuronal survival as well as neurite sprouting of VGNs obtained from younger rats (P1 and P3), whereas these effects were not observed in older rats (P7 and P14). BDNF was also effective in facilitating neurite extension in VGNs at each of the postnatal ages. NT-3 also facilitated neuronal survival and neurite extension of VGNs from younger rats but these effects were significantly smaller than those of BDNF (p < 0.05). The protective effects of BDNF and NT-3 against ototoxic drugs, gentamicin and cisplatin, were also age-dependent: they were effective for neuronal survival, neurite sprouting and neurite extension in VGNs from younger rats, whereas these effects tended to disappear in VGNs from older rats. Analysis of the changes in the expression of the receptors of NTFs revealed that expression of TrkB and TrkC proteins and their mRNA did not change during the developmental period, whereas expression of p75(NTR) protein was down-regulated together with that of p75(NTR) mRNA during the developmental period. Developmental changes in the responsiveness to exogenous NTFs in VGNs, which is not caused by the changes of their receptors but probably caused by changes in the intracellular signaling pathways, should be taken into consideration in the prevention of neuronal degeneration caused by ototoxic drugs.

BDNF prevents NMDA‐induced toxicity in models of Huntington's disease: the effects are genotype specific and adenosine A2A receptor is involved

NMDA receptor-mediated excitotoxicity is thought to play a pivotal role in the pathogenesis of Huntington's disease (HD). The neurotrophin brain-derived neurotrophic factor (BDNF), which is also highly involved in HD and whose effects are modulated by adenosine A2 ARs, influences the activity and expression of striatal NMDA receptors. In electrophysiology experiments, we investigated the role of BDNF toward NMDA-induced effects in HD models, and the possible involvement of A2ARs. In corticostriatal slices from wild-type mice and age-matched symptomatic R6/2 mice (a model of HD), NMDA application (75μM) induced a transient or a permanent (i.e., toxic) reduction of field potential amplitude, respectively. BDNF (10ng/mL) potentiated NMDA effects in wild-type, while it protected from NMDA toxicity in R6/2 mice. Both effects of BDNF were prevented by A2 AR blockade. The protective effect of BDNF against NMDA-induced toxicity was reproduced in a cellular model of HD. These findings may have very important implications for the neuroprotective potential of BDNF and A2 AR ligands in HD.

Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways

Phencyclidine is an N-methyl d-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain-derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration-dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3beta activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3beta at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3beta inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3beta and activation of CREB.

BDNF Effect upon Apoptosis Induced by Amyloid-Beta Peptide: Changes in TRKB Receptors Expression

Event Abstract Back to Event BDNF Effect upon Apoptosis Induced by Amyloid-Beta Peptide: Changes in TRKB Receptors Expression A. S. Jeronimo1*, M. J. Diogenes1, J. A. Ribeiro1 and A. M. Sebastiao1 1 Institute of Molecular Medicine, University of Lisbon, Institute of Pharmacology and Neurosciences, Faculty of Medicine and Neurosciences Unit, Portugal Alzheimer’s disease (AD) is characterized by the deposition of amyloid-beta peptide (Aβ), which has been implicated in the neurodegeneration and neuronal loss observed in AD patients (Shimohama, 2000, Apoptosis 5:9). Brain-derived neurotrophic factor (BDNF) is known to protect neurons through activation of TrkB full length (TrkB-FL) receptors. A decrease in both BDNF and TrkB-FL expression (Connor et al., 1997, Mol Brain Res 49:71) and an increase in TrkB truncated receptors (TrkB-Tc), which lacks signaling domain, have been shown to occur in brain tissue from AD patients (Ferrer et al., 1999, J Neuropathol. Exp. Neurol. 58:729). We therefore hypothesized that Aβ could be one of the causes that lead to the changes in BDNF receptor levels in AD. Thus, in this study we evaluated the influence of Aβ upon the expression of full length and truncated forms of the TrkB receptor in cultured neurons. The protective effect of BDNF upon apoptosis induced by Aβ was also assessed.Primary cortical neuronal cultures were prepared from 18-19-day-old fetuses of Sprague-Dawley rats. Apoptosis was induced by the administration of Aβ25-35 (25μM) on day 4 after plating, and the assays were performed 24h after. BDNF (20 ng/ml) was added 2.5 hours after Aβ25-35. Apoptosis was evaluated through: caspase-3 detection by immunoblot and its activity by spectrophotometric assays. Levels of expression of TrkB receptors were evaluated by immunoblot analysis. The levels of caspase-3 and its activity were low either in neurons under control conditions (without drugs) or in the presence of BDNF alone. When neurons were incubated with Aβ 25-35, there was an approximately a 5-6 fold increase in both the levels and activity of caspase-3 (p<0.01, n=7). When BDNF was added in the presence of Aβ, both formation and activity of caspase-3 were significantly reduced as compared to Aβ alone (-33±5% and -25±6% respectively, n=7, p<0.01). Aβ induced a significant increase in the expression of TrkB- Tc receptors (74±18%, n=7, p<0.01) and a significant decrease in TrkB-FL receptor levels (-37±9%, n=7, p<0.01).We found for the first time that Aβ increases TrkB-Tc and decreases TrkB-FL levels in cultured neurons. Since BDNF protects neurons against Aβ-induced apoptosis, and since protective actions of BDNF are known to occur through TrkB-FL, the results suggest that Aβ-induced neuronal death may be amplified by the concomitant loss of neuroprotection by BDNF. Conference: 11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009. Presentation Type: Poster Presentation Topic: Neurodegenerative Disorders Citation: Jeronimo AS, Diogenes MJ, Ribeiro JA and Sebastiao AM (2009). BDNF Effect upon Apoptosis Induced by Amyloid-Beta Peptide: Changes in TRKB Receptors Expression. Front. Neurosci. Conference Abstract: 11th Meeting of the Portuguese Society for Neuroscience. doi: 10.3389/conf.neuro.01.2009.11.057 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Aug 2009; Published Online: 07 Aug 2009. * Correspondence: A. S Jeronimo, Institute of Molecular Medicine, University of Lisbon, Institute of Pharmacology and Neurosciences, Faculty of Medicine and Neurosciences Unit, Lisbon, Portugal, nemoABS01@frontiersin.org Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers A. S Jeronimo M. J Diogenes J. A Ribeiro A. M Sebastiao Google A. S Jeronimo M. J Diogenes J. A Ribeiro A. M Sebastiao Google Scholar A. S Jeronimo M. J Diogenes J. A Ribeiro A. M Sebastiao PubMed A. S Jeronimo M. J Diogenes J. A Ribeiro A. M Sebastiao Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

BDNF prevents NO mediated glutamate cytotoxicity in cultured cortical neurons

The effects of brain-derived neurotrophic factor (BDNF) on glutamate-induced cytotoxicity were examined using primary cultures of rat cortical neurons. BDNF induced TrkB tyrosine phosphorylation in rat cultured cortical neurons. The cell viability was significantly reduced when cultures were briefly exposed to glutamate and incubated with normal medium for 24 h. Glutamate cytotoxicity was prevented by MK-801, which is a non-competitive blocker of N-methyl- d-aspartate and N ω -nitro- l-arginine, which is a blocker of nitric oxide synthetase. Delayed neurotoxicity was also induced by ionomycin, a calcium ionophore, and nitric oxide (NO) donors such as S-nitrosocysteine (SNOC) and 3-morpholinosydnonimine (SIN-1). Incubating cultures with BDNF for 10 min to 24 h protected cortical neurons against glutamate neurotoxicity. The protective effects of BDNF against glutamate cytotoxicity were dependent on both its concentrations and incubation time. BDNF also prevented the ionomycin-, SNOC-, and SIN-1 induced cytotoxicity. These results indicate that BDNF protects cultured cortical neurons from NMDA receptor-mediated glutamate neurotoxicity by reducing cytotoxic action of NO.

P-532 - Protective effect of BDNF (brain-derived neurotrophic factor) on acrylamide neuropathy in rats.

P-532 - Protective effect of BDNF (brain-derived neurotrophic factor) on acrylamide neuropathy in rats.

Protective effects of BDNF and NT-3 but not PDGF against hypoglycemic injury to cultured striatal neurons

Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and platelet-derived growth factor (PDGF) exert trophic effects on striatal neurons in vitro, which raises the possibility that these growth factors might also counteract neuronal death provoked by various insults. We have found that BDNF and NT-3, but neither PDGF-AA nor -BB, added 24 h before the insult ameliorated hypoglycemic neuronal damage induced by 15 or 24 h of glucose deprivation in rat striatal cell cultures. BDNF and NT-3 afforded neuronal protection even when administered 8 or 4 h, respectively, after the onset of hypoglycemia. In normoglycemic striatal cultures exposed to these neurotrophins for several days, there was a slight, nonsignificant increase of the number of surviving microtubule-associated protein-2-positive cells (20–30%) compared to untreated control cultures, but no change of glial cells. Exposure of the cultures to BDNF or NT-3 produced a significant increase in the number of neurons expressing detectable levels of the calcium-binding protein, calbindin, suggesting that a stabilization of calcium homeostasis might be implicated in the neuroprotection. Immunocytochemical analysis revealed that the majority (70–80%) of neurons in the striatal cultures expressed TrkB and TrkC, the functional receptors for BDNF and NT-3, respectively, implying that the effects of the neurotrophins are most likely direct. These data indicate that BDNF and NT-3 can protect striatal neurons against hypoglycemia in vitro and raise the possibility that these neurotrophins could counteract striatal neuronal death induced by hypoglycemic and ischemic insults in vivo.