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SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aβ Burden in AβPP/PS1 Mice.

Hong ZY, Yu SS, Wang ZJ, Zhu YZ - Int J Mol Sci (2015)

Bottom Line: SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson's disease and Alzheimer's disease (AD).In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198.Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. cerulian@163.com.

ABSTRACT
SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson's disease and Alzheimer's disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1) double-transgenic mice without affecting amyloid-β (Aβ) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

No MeSH data available.


Related in: MedlinePlus

Long-term SCM-198 treatment did not affect amyloid-β (Aβ) burden. Wild-type and AβPP/PS1 mice began receiving different treatments at 6 months of age and were fed continuously for 3 months. All mice were sacrificed after the MWM test and brain slices were stained with rabbit polyclonal anti-Aβ primary antibody and were observed using a confocal microscope. (A) Examples of cortical Aβ staining in AβPP/PS1 mice (green; scale bar, 100 μm; n = 6 mice/group); Cortical soluble Aβ40 (B), soluble Aβ42 (C), insoluble Aβ40 (D) and insoluble Aβ42 (E) levels were measured using ELISA kits (n = 6 mice/group); (F,G) amyloid-β protein precursor (AβPP) expression was analyzed by Western blot (n = 6 mice/group) (SCM: SCM-198). Data represent mean ± SEM. # p < 0.05, ## p < 0.01, ### p < 0.001, Tukey’s test vs. wild-type group.
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ijms-16-18544-f003: Long-term SCM-198 treatment did not affect amyloid-β (Aβ) burden. Wild-type and AβPP/PS1 mice began receiving different treatments at 6 months of age and were fed continuously for 3 months. All mice were sacrificed after the MWM test and brain slices were stained with rabbit polyclonal anti-Aβ primary antibody and were observed using a confocal microscope. (A) Examples of cortical Aβ staining in AβPP/PS1 mice (green; scale bar, 100 μm; n = 6 mice/group); Cortical soluble Aβ40 (B), soluble Aβ42 (C), insoluble Aβ40 (D) and insoluble Aβ42 (E) levels were measured using ELISA kits (n = 6 mice/group); (F,G) amyloid-β protein precursor (AβPP) expression was analyzed by Western blot (n = 6 mice/group) (SCM: SCM-198). Data represent mean ± SEM. # p < 0.05, ## p < 0.01, ### p < 0.001, Tukey’s test vs. wild-type group.

Mentions: Both fluorescent IHC and ELISA methods were applied to investigate whether SCM-198 could decrease Aβ burden in AβPP/PS1 mice brain. Although significant cognitive improvements were observed in NOR and MWM tests, no decrease in Aβ burden was observed after long-term SCM-198 treatment (Figure 3A). Data from ELISA assay showed that significant differences in Aβ40 and Aβ42 levels (F (3, 20) = 175.10, p < 0.0001; F (3, 20) = 108.80, p < 0.0001, respectively, Figure 3B,C) or insoluble Aβ40 and Aβ42 levels (F (3, 20) = 10.92, p = 0.0002; F (3, 20) = 8.571, p = 0.0007, respectively, Figure 3D,E) were only found between the wild-type group and AβPP/PS1 group, and post-hoc analysis showed no differences between SCM-198-treated groups and AβPP/PS1 group. We also analyzed AβPP protein expression by Western blot. Compared with wild-type group, significant increase of AβPP protein expression was observed in AβPP group and SCM-198-treated groups (F (3, 20) = 5.333, p = 0.0073, Figure 3F,G). However, post-hoc analysis also showed no difference in AβPP expression between the AβPP group and SCM-198-treated groups. Overall, SCM-198 has no effects on Aβ load in AβPP/PS1 mouse brain.


SCM-198 Ameliorates Cognitive Deficits, Promotes Neuronal Survival and Enhances CREB/BDNF/TrkB Signaling without Affecting Aβ Burden in AβPP/PS1 Mice.

Hong ZY, Yu SS, Wang ZJ, Zhu YZ - Int J Mol Sci (2015)

Long-term SCM-198 treatment did not affect amyloid-β (Aβ) burden. Wild-type and AβPP/PS1 mice began receiving different treatments at 6 months of age and were fed continuously for 3 months. All mice were sacrificed after the MWM test and brain slices were stained with rabbit polyclonal anti-Aβ primary antibody and were observed using a confocal microscope. (A) Examples of cortical Aβ staining in AβPP/PS1 mice (green; scale bar, 100 μm; n = 6 mice/group); Cortical soluble Aβ40 (B), soluble Aβ42 (C), insoluble Aβ40 (D) and insoluble Aβ42 (E) levels were measured using ELISA kits (n = 6 mice/group); (F,G) amyloid-β protein precursor (AβPP) expression was analyzed by Western blot (n = 6 mice/group) (SCM: SCM-198). Data represent mean ± SEM. # p < 0.05, ## p < 0.01, ### p < 0.001, Tukey’s test vs. wild-type group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4581259&req=5

ijms-16-18544-f003: Long-term SCM-198 treatment did not affect amyloid-β (Aβ) burden. Wild-type and AβPP/PS1 mice began receiving different treatments at 6 months of age and were fed continuously for 3 months. All mice were sacrificed after the MWM test and brain slices were stained with rabbit polyclonal anti-Aβ primary antibody and were observed using a confocal microscope. (A) Examples of cortical Aβ staining in AβPP/PS1 mice (green; scale bar, 100 μm; n = 6 mice/group); Cortical soluble Aβ40 (B), soluble Aβ42 (C), insoluble Aβ40 (D) and insoluble Aβ42 (E) levels were measured using ELISA kits (n = 6 mice/group); (F,G) amyloid-β protein precursor (AβPP) expression was analyzed by Western blot (n = 6 mice/group) (SCM: SCM-198). Data represent mean ± SEM. # p < 0.05, ## p < 0.01, ### p < 0.001, Tukey’s test vs. wild-type group.
Mentions: Both fluorescent IHC and ELISA methods were applied to investigate whether SCM-198 could decrease Aβ burden in AβPP/PS1 mice brain. Although significant cognitive improvements were observed in NOR and MWM tests, no decrease in Aβ burden was observed after long-term SCM-198 treatment (Figure 3A). Data from ELISA assay showed that significant differences in Aβ40 and Aβ42 levels (F (3, 20) = 175.10, p < 0.0001; F (3, 20) = 108.80, p < 0.0001, respectively, Figure 3B,C) or insoluble Aβ40 and Aβ42 levels (F (3, 20) = 10.92, p = 0.0002; F (3, 20) = 8.571, p = 0.0007, respectively, Figure 3D,E) were only found between the wild-type group and AβPP/PS1 group, and post-hoc analysis showed no differences between SCM-198-treated groups and AβPP/PS1 group. We also analyzed AβPP protein expression by Western blot. Compared with wild-type group, significant increase of AβPP protein expression was observed in AβPP group and SCM-198-treated groups (F (3, 20) = 5.333, p = 0.0073, Figure 3F,G). However, post-hoc analysis also showed no difference in AβPP expression between the AβPP group and SCM-198-treated groups. Overall, SCM-198 has no effects on Aβ load in AβPP/PS1 mouse brain.

Bottom Line: SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson's disease and Alzheimer's disease (AD).In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198.Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. cerulian@163.com.

ABSTRACT
SCM-198 is an alkaloid found only in Herba leonuri and it has been reported to possess considerable neuroprotective effects in animal models of ischemic stroke, Parkinson's disease and Alzheimer's disease (AD). In this study, we demonstrated for the first time that 3-month oral SCM-198 treatment could significantly improve both recognition and spatial memory, inhibit microgliosis and promote neuronal survival in amyloid-β protein precursor and presenilin-1(AβPP/PS1) double-transgenic mice without affecting amyloid-β (Aβ) burden. In addition, decreases in cAMP-response element-binding protein (CREB) phosphorylation, brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) phosphorylation were attenuated by SCM-198 both in vivo and in primary cortical neurons, which could be blocked by protein kinase A (PKA) inhibitors, suggesting the involvement of upstream PKA in enhancing the BDNF/TrkB/CREB signaling by SCM-198. Our results indicate that SCM-198, a drug that could promote neuronal survival and enhance BDNF/TrkB/CREB signaling, has beneficial effects on behavioral and biochemical alterations without affecting Aβ burden in AβPP/PS1 mice and might become a potential drug candidate for AD treatment in the future.

No MeSH data available.


Related in: MedlinePlus