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Deoxygedunin, a natural product with potent neurotrophic activity in mice.

Jang SW, Liu X, Chan CB, France SA, Sayeed I, Tang W, Lin X, Xiao G, Andero R, Chang Q, Ressler KJ, Ye K - PLoS ONE (2010)

Bottom Line: Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities.Moreover, deoxygedunin robustly protects rat neurons from cell death in a TrkB-dependent manner.Hence, deoxygedunin imitates BDNF's biological activities through activating TrkB, providing a powerful therapeutic tool for treatment of various neurological diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

ABSTRACT
Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities. Here we report the discovery of deoxygedunin, which activates the mouse TrkB receptor and its downstream signaling cascades. Deoxygedunin is orally available and activates TrkB in mouse brain in a BDNF-independent way. Strikingly, it prevents the degeneration of vestibular ganglion in BDNF -/- pups. Moreover, deoxygedunin robustly protects rat neurons from cell death in a TrkB-dependent manner. Further, administration of deoxygedunin into mice displays potent neuroprotective, anti-depressant and learning enhancement effects, all of which are mediated by the TrkB receptor. Hence, deoxygedunin imitates BDNF's biological activities through activating TrkB, providing a powerful therapeutic tool for treatment of various neurological diseases.

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Related in: MedlinePlus

Deoxygedunin protects neurons from apoptosis in a TrkB-dependent manner.(A) Deoxygedunin prevents glutamate-triggered neuronal apoptosis in wild-type but not TrkB  neurons. Cortical neurons were prepared from the P0 pups (TrkB +/− x TrkB +/−). The neurons were pretreated with a variety of compounds as indicated for 30 min, followed by 50 µM glutamate for 16 h. The cell lysates were analyzed by immunoblotting with anti-p-TrkB, anti-p-TrkA and anti-active caspase-3 etc. (B) Deoxygedunin diminishes caspase-3 activation regardless of TrkC genotype. (C) Deoxygedunin selectively activates TrkB F616A, which can be blocked by 1NMPP1. Primary cortical neurons were prepared from TrkB F616A knockin mice. The primary cultures were pretreated for 30 min with either K252a Trk tyrosine kinase inhibitor (100 nM) or 1NMPP1 inhibitor (100 nM), followed by 0.5 µM Deoxygedunin for 30 min. Immunoblotting with various antibodies were performed. (D) Deoxygedunin suppresses KA-induced neuronal cell death in TrkB F616A mutant mice, which can be blocked by 1NMPP1. TrkB F616A knockin mice were treated with following reagents: saline, 1NMPP1, kainic acid, 1NMPP1 + kainic acid, deoxygedunin, 1NMPP1 + deoxygedunin, 1NMPP1 + deoxygedunin + kainic acid, as described in experimental section. Immunoblotting was conducted with indicated antibodies.
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pone-0011528-g004: Deoxygedunin protects neurons from apoptosis in a TrkB-dependent manner.(A) Deoxygedunin prevents glutamate-triggered neuronal apoptosis in wild-type but not TrkB neurons. Cortical neurons were prepared from the P0 pups (TrkB +/− x TrkB +/−). The neurons were pretreated with a variety of compounds as indicated for 30 min, followed by 50 µM glutamate for 16 h. The cell lysates were analyzed by immunoblotting with anti-p-TrkB, anti-p-TrkA and anti-active caspase-3 etc. (B) Deoxygedunin diminishes caspase-3 activation regardless of TrkC genotype. (C) Deoxygedunin selectively activates TrkB F616A, which can be blocked by 1NMPP1. Primary cortical neurons were prepared from TrkB F616A knockin mice. The primary cultures were pretreated for 30 min with either K252a Trk tyrosine kinase inhibitor (100 nM) or 1NMPP1 inhibitor (100 nM), followed by 0.5 µM Deoxygedunin for 30 min. Immunoblotting with various antibodies were performed. (D) Deoxygedunin suppresses KA-induced neuronal cell death in TrkB F616A mutant mice, which can be blocked by 1NMPP1. TrkB F616A knockin mice were treated with following reagents: saline, 1NMPP1, kainic acid, 1NMPP1 + kainic acid, deoxygedunin, 1NMPP1 + deoxygedunin, 1NMPP1 + deoxygedunin + kainic acid, as described in experimental section. Immunoblotting was conducted with indicated antibodies.

Mentions: To determine if deoxygedunin's neuronal protective effect is mediated through TrkB receptor, we prepared cortical neurons from pups of TrkB +/− mice, which were mated to the same genotype. Deoxygedunin specifically activated TrkB but not TrkA receptor in wild-type but not TrkB −/− neurons. 7,8-dihydroxyflavone (7,8-DHF), another positive compound from the screening, also selectively activated TrkB but not TrkA. The tricyclic antidepressant drugs amitriptyline but not imipramine activated both TrkA and TrkB (Figure 4A, top and 3rd panels). Glutamate-provoked caspase-3 activation was substantially blocked by 7,8-DHF and deoxygedunin in wild-type but not TrkB −/− neurons. However, the control compound imipramine failed to blocked caspase-3 activation by glutamate. In contrast, amitriptyline weakly suppressed caspase-3 activation in both wild-type and TrkB −/− neurons (Figure 4A, bottom panels). Thus, deoxygedunin selectively suppressed apoptosis triggered by glutamate in a TrkB-dependent manner. Moreover, deoxygedunin strongly provoked TrkB but not TrkA activation in both wild-type and TrkC knockout neurons (Figure 4B, top panel). Noticeably, the spontaneous caspase-3 activation in TrkC −/− neurons was suppressed by deoxygedunin. Further, glutamate-triggered caspase-3 activation was significantly diminished by deoxygedunin (Figure 4B, bottom panel), demonstrating that it represses neuronal apoptosis is TrkB- but not TrkC-dependent.


Deoxygedunin, a natural product with potent neurotrophic activity in mice.

Jang SW, Liu X, Chan CB, France SA, Sayeed I, Tang W, Lin X, Xiao G, Andero R, Chang Q, Ressler KJ, Ye K - PLoS ONE (2010)

Deoxygedunin protects neurons from apoptosis in a TrkB-dependent manner.(A) Deoxygedunin prevents glutamate-triggered neuronal apoptosis in wild-type but not TrkB  neurons. Cortical neurons were prepared from the P0 pups (TrkB +/− x TrkB +/−). The neurons were pretreated with a variety of compounds as indicated for 30 min, followed by 50 µM glutamate for 16 h. The cell lysates were analyzed by immunoblotting with anti-p-TrkB, anti-p-TrkA and anti-active caspase-3 etc. (B) Deoxygedunin diminishes caspase-3 activation regardless of TrkC genotype. (C) Deoxygedunin selectively activates TrkB F616A, which can be blocked by 1NMPP1. Primary cortical neurons were prepared from TrkB F616A knockin mice. The primary cultures were pretreated for 30 min with either K252a Trk tyrosine kinase inhibitor (100 nM) or 1NMPP1 inhibitor (100 nM), followed by 0.5 µM Deoxygedunin for 30 min. Immunoblotting with various antibodies were performed. (D) Deoxygedunin suppresses KA-induced neuronal cell death in TrkB F616A mutant mice, which can be blocked by 1NMPP1. TrkB F616A knockin mice were treated with following reagents: saline, 1NMPP1, kainic acid, 1NMPP1 + kainic acid, deoxygedunin, 1NMPP1 + deoxygedunin, 1NMPP1 + deoxygedunin + kainic acid, as described in experimental section. Immunoblotting was conducted with indicated antibodies.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2903477&req=5

pone-0011528-g004: Deoxygedunin protects neurons from apoptosis in a TrkB-dependent manner.(A) Deoxygedunin prevents glutamate-triggered neuronal apoptosis in wild-type but not TrkB neurons. Cortical neurons were prepared from the P0 pups (TrkB +/− x TrkB +/−). The neurons were pretreated with a variety of compounds as indicated for 30 min, followed by 50 µM glutamate for 16 h. The cell lysates were analyzed by immunoblotting with anti-p-TrkB, anti-p-TrkA and anti-active caspase-3 etc. (B) Deoxygedunin diminishes caspase-3 activation regardless of TrkC genotype. (C) Deoxygedunin selectively activates TrkB F616A, which can be blocked by 1NMPP1. Primary cortical neurons were prepared from TrkB F616A knockin mice. The primary cultures were pretreated for 30 min with either K252a Trk tyrosine kinase inhibitor (100 nM) or 1NMPP1 inhibitor (100 nM), followed by 0.5 µM Deoxygedunin for 30 min. Immunoblotting with various antibodies were performed. (D) Deoxygedunin suppresses KA-induced neuronal cell death in TrkB F616A mutant mice, which can be blocked by 1NMPP1. TrkB F616A knockin mice were treated with following reagents: saline, 1NMPP1, kainic acid, 1NMPP1 + kainic acid, deoxygedunin, 1NMPP1 + deoxygedunin, 1NMPP1 + deoxygedunin + kainic acid, as described in experimental section. Immunoblotting was conducted with indicated antibodies.
Mentions: To determine if deoxygedunin's neuronal protective effect is mediated through TrkB receptor, we prepared cortical neurons from pups of TrkB +/− mice, which were mated to the same genotype. Deoxygedunin specifically activated TrkB but not TrkA receptor in wild-type but not TrkB −/− neurons. 7,8-dihydroxyflavone (7,8-DHF), another positive compound from the screening, also selectively activated TrkB but not TrkA. The tricyclic antidepressant drugs amitriptyline but not imipramine activated both TrkA and TrkB (Figure 4A, top and 3rd panels). Glutamate-provoked caspase-3 activation was substantially blocked by 7,8-DHF and deoxygedunin in wild-type but not TrkB −/− neurons. However, the control compound imipramine failed to blocked caspase-3 activation by glutamate. In contrast, amitriptyline weakly suppressed caspase-3 activation in both wild-type and TrkB −/− neurons (Figure 4A, bottom panels). Thus, deoxygedunin selectively suppressed apoptosis triggered by glutamate in a TrkB-dependent manner. Moreover, deoxygedunin strongly provoked TrkB but not TrkA activation in both wild-type and TrkC knockout neurons (Figure 4B, top panel). Noticeably, the spontaneous caspase-3 activation in TrkC −/− neurons was suppressed by deoxygedunin. Further, glutamate-triggered caspase-3 activation was significantly diminished by deoxygedunin (Figure 4B, bottom panel), demonstrating that it represses neuronal apoptosis is TrkB- but not TrkC-dependent.

Bottom Line: Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities.Moreover, deoxygedunin robustly protects rat neurons from cell death in a TrkB-dependent manner.Hence, deoxygedunin imitates BDNF's biological activities through activating TrkB, providing a powerful therapeutic tool for treatment of various neurological diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

ABSTRACT
Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities. Here we report the discovery of deoxygedunin, which activates the mouse TrkB receptor and its downstream signaling cascades. Deoxygedunin is orally available and activates TrkB in mouse brain in a BDNF-independent way. Strikingly, it prevents the degeneration of vestibular ganglion in BDNF -/- pups. Moreover, deoxygedunin robustly protects rat neurons from cell death in a TrkB-dependent manner. Further, administration of deoxygedunin into mice displays potent neuroprotective, anti-depressant and learning enhancement effects, all of which are mediated by the TrkB receptor. Hence, deoxygedunin imitates BDNF's biological activities through activating TrkB, providing a powerful therapeutic tool for treatment of various neurological diseases.

Show MeSH
Related in: MedlinePlus