Limits...
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.

Show MeSH

Related in: MedlinePlus

Deoxygedunin enhances acquisition of conditioned fear, a BDNF-dependent learning process.(A) Outline of Deoxygedunin (DG) fear conditioning experiment. Mice were handled and habituated to testing context on the first two days, followed by systemic DG (5 mg/kg, i.p.) 1 hr prior to fear conditioning (5, 0.5mA shock-tone pairings), followed by testing in the absence of drug on days 4–5. (B) Shock reactivity during fear conditioning, demonstrating that the acute effects of the drug did not affect pain or fear responsiveness. (C) Total freezing to the conditioned cue was significantly greater on both the first and second testing day in the mice that received DG with fear conditioning. (D & E), Freezing activity during the habituation period and first 4 CS presentations on test day 1 (D) or 2 (E). There was no difference in animal activity in the test chamber prior to the onset of the conditioned cue, or between cue presentations. However there was significantly increased fear, as measured with conditioned freezing, during conditioned stimuli (CS). Dark bars represent tone conditioned stimulus presentations; **, p<0.01, *, p<0.05 between DG and vehicle groups.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2903477&req=5

pone-0011528-g007: Deoxygedunin enhances acquisition of conditioned fear, a BDNF-dependent learning process.(A) Outline of Deoxygedunin (DG) fear conditioning experiment. Mice were handled and habituated to testing context on the first two days, followed by systemic DG (5 mg/kg, i.p.) 1 hr prior to fear conditioning (5, 0.5mA shock-tone pairings), followed by testing in the absence of drug on days 4–5. (B) Shock reactivity during fear conditioning, demonstrating that the acute effects of the drug did not affect pain or fear responsiveness. (C) Total freezing to the conditioned cue was significantly greater on both the first and second testing day in the mice that received DG with fear conditioning. (D & E), Freezing activity during the habituation period and first 4 CS presentations on test day 1 (D) or 2 (E). There was no difference in animal activity in the test chamber prior to the onset of the conditioned cue, or between cue presentations. However there was significantly increased fear, as measured with conditioned freezing, during conditioned stimuli (CS). Dark bars represent tone conditioned stimulus presentations; **, p<0.01, *, p<0.05 between DG and vehicle groups.

Mentions: We next wished to examine whether this TrkB agonist would enhance learning in a whole animal model of learning and memory, in which BDNF-dependent TrkB activation is required. Activation of TrkB by BDNF has been repeatedly shown to be associated with, and required for, the acquisition of classical conditioned fear in rodent models [34], [35], [36], [37], [38], [39]. Following habituation to the testing context, 28 adult wild-type, C57BL/6J mice were given systemic injections of deoxygedunin (N = 14, 5 mg/kg, i.p.) or vehicle (N = 14) 1 hr prior to tone-shock fear conditioning in a novel context (Figure 7A). There was no difference between treatment groups in shock reactivity during the fear acquisition training, suggesting that there were no acute effects on pain sensitivity that would affect fear acquisition or later fear expression (p>.1; Figure 7B). Mice were then tested, with no additional drug treatment, for cue-conditioned fear in the previously habituated context on the two days following fear acquisition. The average level of tone-dependent conditioned freezing was significantly different on both testing days (Figure 7C; repeated measures ANOVA, F(1,26) = 6.6, p = .016) suggesting that mice that received deoxygedunin at the time of training had enhanced acquisition or consolidation of the fear memory. To further explore these effects, we examined individual animals' freezing levels throughout the tone-fear testing sessions. We found on both testing day 1 (Figure 7D) and day 2 (Figure 7E) that the enhancement in freezing only corresponded with the periods of tone cue presentation. The mice demonstrated similar levels of locomotor exploratory activity prior to and in-between tone exposure in this context, but the animals that received deoxygedunin during the previous tone-shock fear conditioning demonstrated significantly increased freezing during cued fear presentations (Day 1, repeated measures ANOVA of first 4 CS trials, F(1,26) = 8.1, p<.01; Day 2, F(1,26) = 7.5, p<.01). This increase in fear learning led to a 2–3 fold increase in the level of freezing during the first set of conditioned stimulus (CS) trials examined each day. Together, these results suggest that although deoxygedunin does not affect apparent level of pain or shock reactivity during training, nor does it affect general locomotor activity in the testing situation on subsequent days, the learning event that occurred during training in the presence of systemic deoxygedunin compared with vehicle was acquired or consolidated in a more effective manner. Since cue-dependent fear conditioning is known to require, and be exquisitely sensitive to, BDNF activation of TrkB, these data are consistent with deoxygedunin acting on the TrkB system in vivo to enhance cue-dependent fear learning.


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 enhances acquisition of conditioned fear, a BDNF-dependent learning process.(A) Outline of Deoxygedunin (DG) fear conditioning experiment. Mice were handled and habituated to testing context on the first two days, followed by systemic DG (5 mg/kg, i.p.) 1 hr prior to fear conditioning (5, 0.5mA shock-tone pairings), followed by testing in the absence of drug on days 4–5. (B) Shock reactivity during fear conditioning, demonstrating that the acute effects of the drug did not affect pain or fear responsiveness. (C) Total freezing to the conditioned cue was significantly greater on both the first and second testing day in the mice that received DG with fear conditioning. (D & E), Freezing activity during the habituation period and first 4 CS presentations on test day 1 (D) or 2 (E). There was no difference in animal activity in the test chamber prior to the onset of the conditioned cue, or between cue presentations. However there was significantly increased fear, as measured with conditioned freezing, during conditioned stimuli (CS). Dark bars represent tone conditioned stimulus presentations; **, p<0.01, *, p<0.05 between DG and vehicle groups.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2903477&req=5

pone-0011528-g007: Deoxygedunin enhances acquisition of conditioned fear, a BDNF-dependent learning process.(A) Outline of Deoxygedunin (DG) fear conditioning experiment. Mice were handled and habituated to testing context on the first two days, followed by systemic DG (5 mg/kg, i.p.) 1 hr prior to fear conditioning (5, 0.5mA shock-tone pairings), followed by testing in the absence of drug on days 4–5. (B) Shock reactivity during fear conditioning, demonstrating that the acute effects of the drug did not affect pain or fear responsiveness. (C) Total freezing to the conditioned cue was significantly greater on both the first and second testing day in the mice that received DG with fear conditioning. (D & E), Freezing activity during the habituation period and first 4 CS presentations on test day 1 (D) or 2 (E). There was no difference in animal activity in the test chamber prior to the onset of the conditioned cue, or between cue presentations. However there was significantly increased fear, as measured with conditioned freezing, during conditioned stimuli (CS). Dark bars represent tone conditioned stimulus presentations; **, p<0.01, *, p<0.05 between DG and vehicle groups.
Mentions: We next wished to examine whether this TrkB agonist would enhance learning in a whole animal model of learning and memory, in which BDNF-dependent TrkB activation is required. Activation of TrkB by BDNF has been repeatedly shown to be associated with, and required for, the acquisition of classical conditioned fear in rodent models [34], [35], [36], [37], [38], [39]. Following habituation to the testing context, 28 adult wild-type, C57BL/6J mice were given systemic injections of deoxygedunin (N = 14, 5 mg/kg, i.p.) or vehicle (N = 14) 1 hr prior to tone-shock fear conditioning in a novel context (Figure 7A). There was no difference between treatment groups in shock reactivity during the fear acquisition training, suggesting that there were no acute effects on pain sensitivity that would affect fear acquisition or later fear expression (p>.1; Figure 7B). Mice were then tested, with no additional drug treatment, for cue-conditioned fear in the previously habituated context on the two days following fear acquisition. The average level of tone-dependent conditioned freezing was significantly different on both testing days (Figure 7C; repeated measures ANOVA, F(1,26) = 6.6, p = .016) suggesting that mice that received deoxygedunin at the time of training had enhanced acquisition or consolidation of the fear memory. To further explore these effects, we examined individual animals' freezing levels throughout the tone-fear testing sessions. We found on both testing day 1 (Figure 7D) and day 2 (Figure 7E) that the enhancement in freezing only corresponded with the periods of tone cue presentation. The mice demonstrated similar levels of locomotor exploratory activity prior to and in-between tone exposure in this context, but the animals that received deoxygedunin during the previous tone-shock fear conditioning demonstrated significantly increased freezing during cued fear presentations (Day 1, repeated measures ANOVA of first 4 CS trials, F(1,26) = 8.1, p<.01; Day 2, F(1,26) = 7.5, p<.01). This increase in fear learning led to a 2–3 fold increase in the level of freezing during the first set of conditioned stimulus (CS) trials examined each day. Together, these results suggest that although deoxygedunin does not affect apparent level of pain or shock reactivity during training, nor does it affect general locomotor activity in the testing situation on subsequent days, the learning event that occurred during training in the presence of systemic deoxygedunin compared with vehicle was acquired or consolidated in a more effective manner. Since cue-dependent fear conditioning is known to require, and be exquisitely sensitive to, BDNF activation of TrkB, these data are consistent with deoxygedunin acting on the TrkB system in vivo to enhance cue-dependent fear learning.

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