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Neurogenic and neurotrophic effects of BDNF peptides in mouse hippocampal primary neuronal cell cultures.

Cardenas-Aguayo Mdel C, Kazim SF, Grundke-Iqbal I, Iqbal K - PLoS ONE (2013)

Bottom Line: Peptide B-3, when combined with BDNF, potentiated the survival effect of this neurotrophin on H(2)O(2)-treated E18 hippocampal cells.Peptides B-3 and B-5 were found to work as partial agonists and as partial antagonists competing with BDNF to activate the TrkB receptor in a dose-dependent manner.Taken together, these results suggest that the described BDNF tetra peptides are neurotrophic, can modulate BDNF signaling in a partial agonist/antagonist way, and offer a novel therapeutic approach to neural pathologies where BDNF levels are dysregulated.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.

ABSTRACT
The level of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is down regulated in Alzheimer's disease (AD), Parkinson's disease (PD), depression, stress, and anxiety; conversely the level of this neurotrophin is increased in autism spectrum disorders. Thus, modulating the level of BDNF can be a potential therapeutic approach for nervous system pathologies. In the present study, we designed five different tetra peptides (peptides B-1 to B-5) corresponding to different active regions of BDNF. These tetra peptides were found to be non-toxic, and they induced the expression of neuronal markers in mouse embryonic day 18 (E18) primary hippocampal neuronal cultures. Additionally, peptide B-5 induced the expression of BDNF and its receptor, TrkB, suggesting a positive feedback mechanism. The BDNF peptides induced only a moderate activation (phosphorylation at Tyr 706) of the TrkB receptor, which could be blocked by the Trk's inhibitor, K252a. Peptide B-3, when combined with BDNF, potentiated the survival effect of this neurotrophin on H(2)O(2)-treated E18 hippocampal cells. Peptides B-3 and B-5 were found to work as partial agonists and as partial antagonists competing with BDNF to activate the TrkB receptor in a dose-dependent manner. Taken together, these results suggest that the described BDNF tetra peptides are neurotrophic, can modulate BDNF signaling in a partial agonist/antagonist way, and offer a novel therapeutic approach to neural pathologies where BDNF levels are dysregulated.

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Proposed mechanism of action of BDNF peptides.BDNF peptides B-5 and B-3 may interact with or compete for the binding site of BDNF to its transmembrane receptor TrkB. Depending on the concentration or the cellular state or condition (i.e. during stress, like in the presence of H2O2), the peptides could act as partial agonists or partial antagonists. Fig. 8A shows the partial agonistic role of the peptides. In this case, the peptides favor the activation of the TrkB receptor, and in the presence of BDNF, they synergize with it. Once the TrkB receptor gets activated, it is dimerized and autophosphorylated (one of the residues that gets phosphorylated is the Tyr 706) and the signal is transduced. The cascades that could be activated by the peptides include the differentiation pathway through MAPK and pCREB regulating gene expression of markers of neuronal phenotype and plasticity, and also the expression of BDNF and TrkB, giving the possibility of a feedback mechanism. The other cascade that could be activated by the peptides is the survival one, in which PI3K and AKT participate to enhance survival and inhibit cell death. Fig. 8B represents the partial antagonistic role of the peptides where the peptides compete with BDNF for the activation of the receptor blocking the TrkB activation by BDNF and its signal transduction pathway. The sites where the TrkB inhibitor K252a and the protein synthesis inhibitor CHX can block the pathway are shown with a grey and red bar, respectively.
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pone-0053596-g009: Proposed mechanism of action of BDNF peptides.BDNF peptides B-5 and B-3 may interact with or compete for the binding site of BDNF to its transmembrane receptor TrkB. Depending on the concentration or the cellular state or condition (i.e. during stress, like in the presence of H2O2), the peptides could act as partial agonists or partial antagonists. Fig. 8A shows the partial agonistic role of the peptides. In this case, the peptides favor the activation of the TrkB receptor, and in the presence of BDNF, they synergize with it. Once the TrkB receptor gets activated, it is dimerized and autophosphorylated (one of the residues that gets phosphorylated is the Tyr 706) and the signal is transduced. The cascades that could be activated by the peptides include the differentiation pathway through MAPK and pCREB regulating gene expression of markers of neuronal phenotype and plasticity, and also the expression of BDNF and TrkB, giving the possibility of a feedback mechanism. The other cascade that could be activated by the peptides is the survival one, in which PI3K and AKT participate to enhance survival and inhibit cell death. Fig. 8B represents the partial antagonistic role of the peptides where the peptides compete with BDNF for the activation of the receptor blocking the TrkB activation by BDNF and its signal transduction pathway. The sites where the TrkB inhibitor K252a and the protein synthesis inhibitor CHX can block the pathway are shown with a grey and red bar, respectively.

Mentions: The proposed mechanism of action of the BDNF peptides, B-5 and B-3, is that they may interact or compete for the binding site of BDNF to its transmembrane receptor TrkB (Fig. 9). Depending on the concentration or the cellular state (for instance, during stress, like in the presence of H2O2), they could act as partial agonist or partial antagonists. Alternatively, they might also activate other receptors (which remain to be investigated). Once the TrkB receptor gets activated, it is dimerized and autophosphorylated (one of the residues that gets phosphorylated is the Tyr 706), afterwards, the signal is transduced, and two principal cascades can be activated, (i) the differentiation pathway through MAPK and pCREB, regulating gene expression of markers of neuronal phenotype and plasticity, and also the expression of BDNF and TrkB resulting in the possibility of a feedback mechanism; and (ii) the cascade involving PI3K and AKT that regulates survival and cell death. Alternatively, the BDNF pathway can activate the PLC-γ signaling that is involved in activity dependent plasticity. The increase in expression of BDNF and TrkB by Peptides B-5 and B-3 probably work like a feedback system. The inhibitor K252a blocks the activation of TrkB at the beginning of the pathway, and CHX blocks the protein synthesis at the end of the pathway (Fig. 9).


Neurogenic and neurotrophic effects of BDNF peptides in mouse hippocampal primary neuronal cell cultures.

Cardenas-Aguayo Mdel C, Kazim SF, Grundke-Iqbal I, Iqbal K - PLoS ONE (2013)

Proposed mechanism of action of BDNF peptides.BDNF peptides B-5 and B-3 may interact with or compete for the binding site of BDNF to its transmembrane receptor TrkB. Depending on the concentration or the cellular state or condition (i.e. during stress, like in the presence of H2O2), the peptides could act as partial agonists or partial antagonists. Fig. 8A shows the partial agonistic role of the peptides. In this case, the peptides favor the activation of the TrkB receptor, and in the presence of BDNF, they synergize with it. Once the TrkB receptor gets activated, it is dimerized and autophosphorylated (one of the residues that gets phosphorylated is the Tyr 706) and the signal is transduced. The cascades that could be activated by the peptides include the differentiation pathway through MAPK and pCREB regulating gene expression of markers of neuronal phenotype and plasticity, and also the expression of BDNF and TrkB, giving the possibility of a feedback mechanism. The other cascade that could be activated by the peptides is the survival one, in which PI3K and AKT participate to enhance survival and inhibit cell death. Fig. 8B represents the partial antagonistic role of the peptides where the peptides compete with BDNF for the activation of the receptor blocking the TrkB activation by BDNF and its signal transduction pathway. The sites where the TrkB inhibitor K252a and the protein synthesis inhibitor CHX can block the pathway are shown with a grey and red bar, respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3539976&req=5

pone-0053596-g009: Proposed mechanism of action of BDNF peptides.BDNF peptides B-5 and B-3 may interact with or compete for the binding site of BDNF to its transmembrane receptor TrkB. Depending on the concentration or the cellular state or condition (i.e. during stress, like in the presence of H2O2), the peptides could act as partial agonists or partial antagonists. Fig. 8A shows the partial agonistic role of the peptides. In this case, the peptides favor the activation of the TrkB receptor, and in the presence of BDNF, they synergize with it. Once the TrkB receptor gets activated, it is dimerized and autophosphorylated (one of the residues that gets phosphorylated is the Tyr 706) and the signal is transduced. The cascades that could be activated by the peptides include the differentiation pathway through MAPK and pCREB regulating gene expression of markers of neuronal phenotype and plasticity, and also the expression of BDNF and TrkB, giving the possibility of a feedback mechanism. The other cascade that could be activated by the peptides is the survival one, in which PI3K and AKT participate to enhance survival and inhibit cell death. Fig. 8B represents the partial antagonistic role of the peptides where the peptides compete with BDNF for the activation of the receptor blocking the TrkB activation by BDNF and its signal transduction pathway. The sites where the TrkB inhibitor K252a and the protein synthesis inhibitor CHX can block the pathway are shown with a grey and red bar, respectively.
Mentions: The proposed mechanism of action of the BDNF peptides, B-5 and B-3, is that they may interact or compete for the binding site of BDNF to its transmembrane receptor TrkB (Fig. 9). Depending on the concentration or the cellular state (for instance, during stress, like in the presence of H2O2), they could act as partial agonist or partial antagonists. Alternatively, they might also activate other receptors (which remain to be investigated). Once the TrkB receptor gets activated, it is dimerized and autophosphorylated (one of the residues that gets phosphorylated is the Tyr 706), afterwards, the signal is transduced, and two principal cascades can be activated, (i) the differentiation pathway through MAPK and pCREB, regulating gene expression of markers of neuronal phenotype and plasticity, and also the expression of BDNF and TrkB resulting in the possibility of a feedback mechanism; and (ii) the cascade involving PI3K and AKT that regulates survival and cell death. Alternatively, the BDNF pathway can activate the PLC-γ signaling that is involved in activity dependent plasticity. The increase in expression of BDNF and TrkB by Peptides B-5 and B-3 probably work like a feedback system. The inhibitor K252a blocks the activation of TrkB at the beginning of the pathway, and CHX blocks the protein synthesis at the end of the pathway (Fig. 9).

Bottom Line: Peptide B-3, when combined with BDNF, potentiated the survival effect of this neurotrophin on H(2)O(2)-treated E18 hippocampal cells.Peptides B-3 and B-5 were found to work as partial agonists and as partial antagonists competing with BDNF to activate the TrkB receptor in a dose-dependent manner.Taken together, these results suggest that the described BDNF tetra peptides are neurotrophic, can modulate BDNF signaling in a partial agonist/antagonist way, and offer a novel therapeutic approach to neural pathologies where BDNF levels are dysregulated.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.

ABSTRACT
The level of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is down regulated in Alzheimer's disease (AD), Parkinson's disease (PD), depression, stress, and anxiety; conversely the level of this neurotrophin is increased in autism spectrum disorders. Thus, modulating the level of BDNF can be a potential therapeutic approach for nervous system pathologies. In the present study, we designed five different tetra peptides (peptides B-1 to B-5) corresponding to different active regions of BDNF. These tetra peptides were found to be non-toxic, and they induced the expression of neuronal markers in mouse embryonic day 18 (E18) primary hippocampal neuronal cultures. Additionally, peptide B-5 induced the expression of BDNF and its receptor, TrkB, suggesting a positive feedback mechanism. The BDNF peptides induced only a moderate activation (phosphorylation at Tyr 706) of the TrkB receptor, which could be blocked by the Trk's inhibitor, K252a. Peptide B-3, when combined with BDNF, potentiated the survival effect of this neurotrophin on H(2)O(2)-treated E18 hippocampal cells. Peptides B-3 and B-5 were found to work as partial agonists and as partial antagonists competing with BDNF to activate the TrkB receptor in a dose-dependent manner. Taken together, these results suggest that the described BDNF tetra peptides are neurotrophic, can modulate BDNF signaling in a partial agonist/antagonist way, and offer a novel therapeutic approach to neural pathologies where BDNF levels are dysregulated.

Show MeSH
Related in: MedlinePlus