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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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BDNF tetrapeptides used in this study.(A) Amino acid sequence of human BDNF. The signal peptide (18 amino acids, positions 1–18) is shown in green, the propeptide (110 amino acids, positions 19–128) in blue, and the BDNF sequence, (119 amino acids, positions 129–247, molecular weight 26 kDa) in black. The sequences of the 5 tetra peptides used in this study (B-1 to B-5) are boxed (as red squares). (B) Chemical structures of the BDNF peptides used in this study.
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pone-0053596-g001: BDNF tetrapeptides used in this study.(A) Amino acid sequence of human BDNF. The signal peptide (18 amino acids, positions 1–18) is shown in green, the propeptide (110 amino acids, positions 19–128) in blue, and the BDNF sequence, (119 amino acids, positions 129–247, molecular weight 26 kDa) in black. The sequences of the 5 tetra peptides used in this study (B-1 to B-5) are boxed (as red squares). (B) Chemical structures of the BDNF peptides used in this study.

Mentions: (http://uniprot.org/uniprot/P23560), we identified different active regions of BDNF. We then narrowed down the active regions, and synthesized five druggable tetra peptides corresponding to amino acid residues 6–9, 71–74, 72–75, 94–97 and 115–118 of human BDNF (Figure 1A and B). Peptides B-1 to B-5 were N-terminally acetylated and C-terminally amidated (Fig. 1B). The sequences of these peptides are as follows: Peptide B-5 (Ac-I-K-R-G-CONH2 corresponding to amino acids (AAs) 243–246 of pro BDNF and AAs 115–118 of BDNF), molecular weight 513.63; Peptide B- 4 (Ac-D-K-R-H-CONH2 corresponding to AAs 200–203 of pro BDNF and AAs 72–75 of BDNF), molecular weight 595.65; Peptide B-3 (Ac-S-K-K-R-CONH2 corresponding to AAs 222–225 of pro BDNF and AAs 94–97 of BDNF), molecular weight 558.67; Peptide B-2 (Ac-I-D-K-R-CONH2 corresponding to AAs 193–196 of pro BDNF and AAs 71–74 of BDNF), molecular weight 571.67; and Peptide B-1(Ac-R-R-G-E-CONH2 corresponding to AAs 134–137 of pro BDNF and AAs 6–9 of BDNF), molecular weight 557.6 (Fig. 1A). These peptides were synthesized at Stanford University Protein and Nucleic Acid Research Lab on a commercial basis. All peptides were purified by HPLC to 95–99% of purity and their identity was confirmed by mass spectrometry. The synthetic peptides were soluble in water.


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)

BDNF tetrapeptides used in this study.(A) Amino acid sequence of human BDNF. The signal peptide (18 amino acids, positions 1–18) is shown in green, the propeptide (110 amino acids, positions 19–128) in blue, and the BDNF sequence, (119 amino acids, positions 129–247, molecular weight 26 kDa) in black. The sequences of the 5 tetra peptides used in this study (B-1 to B-5) are boxed (as red squares). (B) Chemical structures of the BDNF peptides used in this study.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3539976&req=5

pone-0053596-g001: BDNF tetrapeptides used in this study.(A) Amino acid sequence of human BDNF. The signal peptide (18 amino acids, positions 1–18) is shown in green, the propeptide (110 amino acids, positions 19–128) in blue, and the BDNF sequence, (119 amino acids, positions 129–247, molecular weight 26 kDa) in black. The sequences of the 5 tetra peptides used in this study (B-1 to B-5) are boxed (as red squares). (B) Chemical structures of the BDNF peptides used in this study.
Mentions: (http://uniprot.org/uniprot/P23560), we identified different active regions of BDNF. We then narrowed down the active regions, and synthesized five druggable tetra peptides corresponding to amino acid residues 6–9, 71–74, 72–75, 94–97 and 115–118 of human BDNF (Figure 1A and B). Peptides B-1 to B-5 were N-terminally acetylated and C-terminally amidated (Fig. 1B). The sequences of these peptides are as follows: Peptide B-5 (Ac-I-K-R-G-CONH2 corresponding to amino acids (AAs) 243–246 of pro BDNF and AAs 115–118 of BDNF), molecular weight 513.63; Peptide B- 4 (Ac-D-K-R-H-CONH2 corresponding to AAs 200–203 of pro BDNF and AAs 72–75 of BDNF), molecular weight 595.65; Peptide B-3 (Ac-S-K-K-R-CONH2 corresponding to AAs 222–225 of pro BDNF and AAs 94–97 of BDNF), molecular weight 558.67; Peptide B-2 (Ac-I-D-K-R-CONH2 corresponding to AAs 193–196 of pro BDNF and AAs 71–74 of BDNF), molecular weight 571.67; and Peptide B-1(Ac-R-R-G-E-CONH2 corresponding to AAs 134–137 of pro BDNF and AAs 6–9 of BDNF), molecular weight 557.6 (Fig. 1A). These peptides were synthesized at Stanford University Protein and Nucleic Acid Research Lab on a commercial basis. All peptides were purified by HPLC to 95–99% of purity and their identity was confirmed by mass spectrometry. The synthetic peptides were soluble in water.

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