Limits...
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

SCM-198 alleviated excessive microglial activation and decreased TNF-α levels in AβPP/PS1 mice. Wild-type and AβPP/PS1 mice began receiving different treatments at 6 months of age and were fed continuously for 3 months. Microgliosis was visualized by fluorescent immunostaining after behavioral tests. (A) Cortical (upper panel) and hippocampal (lower panel) microglia were stained using goat polyclonal anti-iba-1antibody (red; scale bar, 100 μm) and were observed using a confocal microscope; (B) Representative confocal images of microglia (iba-1; red) and senile plaques (Aβ; green) in 9-month-old AβPP/PS1 mice (scale bar, 20 μm); (C) Integrated optical density (IOD) of cortical iba-1 staining (n = 6 mice/group); (D) IOD of hippocampal iba-1staining (n = 6 mice/group); (E) Cortical tumor necrosis factor-α (TNF-α) was measured with commercial ELISA kits (n = 6 mice/group). Data represent mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, Tukey’s test vs. AβPP/PS1 group; ### p < 0.001, Tukey’s test vs. wild-type group.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581259&req=5

ijms-16-18544-f004: SCM-198 alleviated excessive microglial activation and decreased TNF-α levels in AβPP/PS1 mice. Wild-type and AβPP/PS1 mice began receiving different treatments at 6 months of age and were fed continuously for 3 months. Microgliosis was visualized by fluorescent immunostaining after behavioral tests. (A) Cortical (upper panel) and hippocampal (lower panel) microglia were stained using goat polyclonal anti-iba-1antibody (red; scale bar, 100 μm) and were observed using a confocal microscope; (B) Representative confocal images of microglia (iba-1; red) and senile plaques (Aβ; green) in 9-month-old AβPP/PS1 mice (scale bar, 20 μm); (C) Integrated optical density (IOD) of cortical iba-1 staining (n = 6 mice/group); (D) IOD of hippocampal iba-1staining (n = 6 mice/group); (E) Cortical tumor necrosis factor-α (TNF-α) was measured with commercial ELISA kits (n = 6 mice/group). Data represent mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, Tukey’s test vs. AβPP/PS1 group; ### p < 0.001, Tukey’s test vs. wild-type group.

Mentions: As excessive chronic neuroinflammation is now considered one of the major risk factors in the development of AD, we assessed microglial activation in both cortex and hippocampus of AβPP/PS1 mice. As can be seen in Figure 4A, marked increases in microgliosis in both cortex and hippocampus were observed in vehicle-treated AβPP/PS1 mice as compared with those of wild-type mice. SCM-198 at doses of 50 and 100 mg/kg significantly reduced microglial overactivation in the cortex (F (3, 116) = 52.65, p < 0.0001, Figure 4C) and hippocampus (F (3, 116) = 15.07, p < 0.0001, Figure 4D). Aggregation and recruitment of microglial cells with large cellular bodies around the amyloid plaques were observed in both vehicle- and SCM-198-treated AβPP/PS1 mice. Strong immunoreactivity of iba-1 is still evident in microglial cells that are far from the plaques in vehicle-treated AβPP/PS1 mice, whereas this strong iba-1 immunoreactivity was less pronounced in SCM-198-treated group (Figure 4B). ELISA assay showed that cortical TNF-α, one of the proinflammatory cytokines released by overactivated microglia, significantly increased in vehicle-treated AβPP/PS1 mice, while 50 and 100 mg/kg SCM-198 prevented TNF-α elevation in a dose-dependent manner (F (3, 20) = 13.23, p < 0.0001, Figure 4E), which was consistent with the results of immunostaining of microglia.


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)

SCM-198 alleviated excessive microglial activation and decreased TNF-α levels in AβPP/PS1 mice. Wild-type and AβPP/PS1 mice began receiving different treatments at 6 months of age and were fed continuously for 3 months. Microgliosis was visualized by fluorescent immunostaining after behavioral tests. (A) Cortical (upper panel) and hippocampal (lower panel) microglia were stained using goat polyclonal anti-iba-1antibody (red; scale bar, 100 μm) and were observed using a confocal microscope; (B) Representative confocal images of microglia (iba-1; red) and senile plaques (Aβ; green) in 9-month-old AβPP/PS1 mice (scale bar, 20 μm); (C) Integrated optical density (IOD) of cortical iba-1 staining (n = 6 mice/group); (D) IOD of hippocampal iba-1staining (n = 6 mice/group); (E) Cortical tumor necrosis factor-α (TNF-α) was measured with commercial ELISA kits (n = 6 mice/group). Data represent mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, Tukey’s test vs. AβPP/PS1 group; ### p < 0.001, Tukey’s test vs. wild-type group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581259&req=5

ijms-16-18544-f004: SCM-198 alleviated excessive microglial activation and decreased TNF-α levels in AβPP/PS1 mice. Wild-type and AβPP/PS1 mice began receiving different treatments at 6 months of age and were fed continuously for 3 months. Microgliosis was visualized by fluorescent immunostaining after behavioral tests. (A) Cortical (upper panel) and hippocampal (lower panel) microglia were stained using goat polyclonal anti-iba-1antibody (red; scale bar, 100 μm) and were observed using a confocal microscope; (B) Representative confocal images of microglia (iba-1; red) and senile plaques (Aβ; green) in 9-month-old AβPP/PS1 mice (scale bar, 20 μm); (C) Integrated optical density (IOD) of cortical iba-1 staining (n = 6 mice/group); (D) IOD of hippocampal iba-1staining (n = 6 mice/group); (E) Cortical tumor necrosis factor-α (TNF-α) was measured with commercial ELISA kits (n = 6 mice/group). Data represent mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, Tukey’s test vs. AβPP/PS1 group; ### p < 0.001, Tukey’s test vs. wild-type group.
Mentions: As excessive chronic neuroinflammation is now considered one of the major risk factors in the development of AD, we assessed microglial activation in both cortex and hippocampus of AβPP/PS1 mice. As can be seen in Figure 4A, marked increases in microgliosis in both cortex and hippocampus were observed in vehicle-treated AβPP/PS1 mice as compared with those of wild-type mice. SCM-198 at doses of 50 and 100 mg/kg significantly reduced microglial overactivation in the cortex (F (3, 116) = 52.65, p < 0.0001, Figure 4C) and hippocampus (F (3, 116) = 15.07, p < 0.0001, Figure 4D). Aggregation and recruitment of microglial cells with large cellular bodies around the amyloid plaques were observed in both vehicle- and SCM-198-treated AβPP/PS1 mice. Strong immunoreactivity of iba-1 is still evident in microglial cells that are far from the plaques in vehicle-treated AβPP/PS1 mice, whereas this strong iba-1 immunoreactivity was less pronounced in SCM-198-treated group (Figure 4B). ELISA assay showed that cortical TNF-α, one of the proinflammatory cytokines released by overactivated microglia, significantly increased in vehicle-treated AβPP/PS1 mice, while 50 and 100 mg/kg SCM-198 prevented TNF-α elevation in a dose-dependent manner (F (3, 20) = 13.23, p < 0.0001, Figure 4E), which was consistent with the results of immunostaining of microglia.

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