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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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Deoxygedunin activates TrkB in a BDNF-independent manner and prevents vestibular ganglion loss.(A) Deoxygedunin triggers TrkB activation in BDNF conditional knockout cortex. 2–3 months old BDNF cortex conditional knockout mice were intraperitoneally injected with 5 mg/kg deoxygedunin. In 4 h, the mice were sacrificed and brain lysates were analyzed by immunoblotting. (B & C) Deoxygedunin and 7,8-DHF prevent vestibular ganglion loss in BDNF −/− pups. BDNF +/− mice were mated with the same genotypes of mice. At E7.5 days, the pregnant mothers were administrated with 5 mg/kg deoxygedunin or 7,8-DHF until birth. The neonatal pups continued on drug treatment for 1 or 2 days till death. The inner ear sections were stained with toluidine blue.
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pone-0011528-g005: Deoxygedunin activates TrkB in a BDNF-independent manner and prevents vestibular ganglion loss.(A) Deoxygedunin triggers TrkB activation in BDNF conditional knockout cortex. 2–3 months old BDNF cortex conditional knockout mice were intraperitoneally injected with 5 mg/kg deoxygedunin. In 4 h, the mice were sacrificed and brain lysates were analyzed by immunoblotting. (B & C) Deoxygedunin and 7,8-DHF prevent vestibular ganglion loss in BDNF −/− pups. BDNF +/− mice were mated with the same genotypes of mice. At E7.5 days, the pregnant mothers were administrated with 5 mg/kg deoxygedunin or 7,8-DHF until birth. The neonatal pups continued on drug treatment for 1 or 2 days till death. The inner ear sections were stained with toluidine blue.

Mentions: To examine whether deoxygedunin activating TrkB involves endogenous BDNF, we employed BDNF conditional knockout mice with BDNF gene deletion limited to cortex, thus allowing normal development. We intraperitoneally injected deoxygedunin (5 mg/kg) into BDNF cortex conditional knockout mice and sacrificed the mice at 4 h. Immunoblotting analysis with the cortical lysates demonstrated robust TrkB activation in both wild-type and BDNF −/− mice (Figure 5A), underscoring that deoxygedunin activates TrkB independent of BDNF. Mutant mice lacking BDNF have severe deficiencies in coordination and balance, associated with excessive degeneration in several sensory ganglia including the vestibular ganglion [25]. To determine whether deoxygedunin rescues the loss of vestibular ganglions in BDNF −/− pups, we bred the conventional BDNF +/− mice with the same genotype mice, and administered deoxygedunin (5 mg/kg, i.p.) to the pregnant mice at day E7.5 until birth. The neonatal pups continued receiving the same dose of deoxygedunin, but BDNF −/− pups continued dying at P1 or P2. Staining of inner ear sections showed that vestibular ganglia were completely lost in most of control vehicle-treated BDNF −/− pups. In contrast, many of deoxygedunin-treated BDNF mutant mice displayed intact vestibular ganglia, similar to the wild-type pups (Figure 5B, left panels). Quantitative analysis demonstrated that 9.1% of vestibular ganglia were detected in vehicle-treated BDNF −/− pups, whereas deoxygedunin treatment increased to 42.2% (Figure 5B, right panel). We made a similar observation with 7,8-DHF (Figure 5C). Therefore, deoxygedunin mimics BDNF and significantly protects vestibular ganglia from degeneration in BDNF -/- pups.


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 activates TrkB in a BDNF-independent manner and prevents vestibular ganglion loss.(A) Deoxygedunin triggers TrkB activation in BDNF conditional knockout cortex. 2–3 months old BDNF cortex conditional knockout mice were intraperitoneally injected with 5 mg/kg deoxygedunin. In 4 h, the mice were sacrificed and brain lysates were analyzed by immunoblotting. (B & C) Deoxygedunin and 7,8-DHF prevent vestibular ganglion loss in BDNF −/− pups. BDNF +/− mice were mated with the same genotypes of mice. At E7.5 days, the pregnant mothers were administrated with 5 mg/kg deoxygedunin or 7,8-DHF until birth. The neonatal pups continued on drug treatment for 1 or 2 days till death. The inner ear sections were stained with toluidine blue.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2903477&req=5

pone-0011528-g005: Deoxygedunin activates TrkB in a BDNF-independent manner and prevents vestibular ganglion loss.(A) Deoxygedunin triggers TrkB activation in BDNF conditional knockout cortex. 2–3 months old BDNF cortex conditional knockout mice were intraperitoneally injected with 5 mg/kg deoxygedunin. In 4 h, the mice were sacrificed and brain lysates were analyzed by immunoblotting. (B & C) Deoxygedunin and 7,8-DHF prevent vestibular ganglion loss in BDNF −/− pups. BDNF +/− mice were mated with the same genotypes of mice. At E7.5 days, the pregnant mothers were administrated with 5 mg/kg deoxygedunin or 7,8-DHF until birth. The neonatal pups continued on drug treatment for 1 or 2 days till death. The inner ear sections were stained with toluidine blue.
Mentions: To examine whether deoxygedunin activating TrkB involves endogenous BDNF, we employed BDNF conditional knockout mice with BDNF gene deletion limited to cortex, thus allowing normal development. We intraperitoneally injected deoxygedunin (5 mg/kg) into BDNF cortex conditional knockout mice and sacrificed the mice at 4 h. Immunoblotting analysis with the cortical lysates demonstrated robust TrkB activation in both wild-type and BDNF −/− mice (Figure 5A), underscoring that deoxygedunin activates TrkB independent of BDNF. Mutant mice lacking BDNF have severe deficiencies in coordination and balance, associated with excessive degeneration in several sensory ganglia including the vestibular ganglion [25]. To determine whether deoxygedunin rescues the loss of vestibular ganglions in BDNF −/− pups, we bred the conventional BDNF +/− mice with the same genotype mice, and administered deoxygedunin (5 mg/kg, i.p.) to the pregnant mice at day E7.5 until birth. The neonatal pups continued receiving the same dose of deoxygedunin, but BDNF −/− pups continued dying at P1 or P2. Staining of inner ear sections showed that vestibular ganglia were completely lost in most of control vehicle-treated BDNF −/− pups. In contrast, many of deoxygedunin-treated BDNF mutant mice displayed intact vestibular ganglia, similar to the wild-type pups (Figure 5B, left panels). Quantitative analysis demonstrated that 9.1% of vestibular ganglia were detected in vehicle-treated BDNF −/− pups, whereas deoxygedunin treatment increased to 42.2% (Figure 5B, right panel). We made a similar observation with 7,8-DHF (Figure 5C). Therefore, deoxygedunin mimics BDNF and significantly protects vestibular ganglia from degeneration in BDNF -/- pups.

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