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Synergistic Neuroprotective Effects of Two Herbal Ingredients via CREB-Dependent Pathway

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ABSTRACT

As two natural oligosaccharide esters, 3,6’-Disinapoyl sucrose (DISS) and tenuifolisideA (TFSA) are originating from the root of Polygala tenuifolia Willd, a traditional Chinese medicine used in treatment of mental disorders. Previous reports have shown that both of them possess in vitro neuroprotective effects by stimulating different upstream pathways related with cyclic AMP-responsive element-binding protein (CREB). In the present study, we investigated the additive neuroprotective effects of DISS and TFSA on Glu-induced damage of SY5Y cells and purposed the possible underlying mechanism. The interaction between DISS and TFSA showed a clear-cut synergistic effect as evidenced by combination index (CI). Additional evidence from biochemical (NOS activity) assays confirmed their additive inhibition on the Glu-induced NOS hyperactivation. Moreover, we showed that co-treatment of DISS and TFSA resulted in an additively up-regulated phosphorylation of CREB as well as increased expressions of CRTC1 and BDNF. Neuroprotective effects of DISS and TFSA on Glu-induced decrease in cell viability were blocked by MAPK/ERK1/2 inhibitor (U0126) and PI3-K inhibitor (LY290042). Nevertheless, the CRTC1 or BDNF expression induced by these two compounds was significantly reduced in the presence of either ERK or PI3-K inhibitor, indicating that the two oligosaccharide esters shared some common pathways in the regulation of CREB-BDNF pathway. Taken together, we, for the first time, showed that DISS and TFSA exerted the additive neuroprotective effects on CREB-BDNF signaling pathway through complementary mechanisms.

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Inhibitory effect of ERK1/2 and PI3K on DISS- or TFSA-induced BDNF and CRTC1 expressions in SY5Y cells (n = 9). SY5Y cells were pretreated with 10 μM U0126 or 30 μM LY294002 for 30 min, followed by treatment with 150 μM DISS or 50 μM TFSA for 48 h. (A) Expressions of BDNF and CRTC1 were examined by western blotting. (B) The expression of BDNF and CRTC1. Data were expressed as mean ± SD. ∗p < 0.05 and ∗∗p < 0.01 compared with the untreated control group. #p < 0.05 compared with its compound alone.
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Figure 4: Inhibitory effect of ERK1/2 and PI3K on DISS- or TFSA-induced BDNF and CRTC1 expressions in SY5Y cells (n = 9). SY5Y cells were pretreated with 10 μM U0126 or 30 μM LY294002 for 30 min, followed by treatment with 150 μM DISS or 50 μM TFSA for 48 h. (A) Expressions of BDNF and CRTC1 were examined by western blotting. (B) The expression of BDNF and CRTC1. Data were expressed as mean ± SD. ∗p < 0.05 and ∗∗p < 0.01 compared with the untreated control group. #p < 0.05 compared with its compound alone.

Mentions: Considering the various CREB pathways activated by DISS and TFSA, we assessed the signaling mechanisms involved in CRTC1 and BDNF regulation using two inhibitors. Figure 4 reveals that treatment of DISS or TFSA increased the expression of BDNF and CRTC1, but such an increase could be partially attenuated by either U0126 or LY294002. PI3-K inhibitor LY294003 showed a similar but weaker inhibitory effect on DISS-induced CRTC1 expression compared with U0126 (Figure 4A). The LY294002 decreased the DISS- or TFSA-induced BDNF expression by 47 and 25%, respectively. The ERK1/2 inhibitor U0126 decreased the DISS- or TFSA-induced BDNF expression by 25 and 21%, respectively. (Figure 4B). A bigger decrease in DISS- or TFSA-induced BDNF expression was caused by LY294003 compared with U0126 (Figure 4B).


Synergistic Neuroprotective Effects of Two Herbal Ingredients via CREB-Dependent Pathway
Inhibitory effect of ERK1/2 and PI3K on DISS- or TFSA-induced BDNF and CRTC1 expressions in SY5Y cells (n = 9). SY5Y cells were pretreated with 10 μM U0126 or 30 μM LY294002 for 30 min, followed by treatment with 150 μM DISS or 50 μM TFSA for 48 h. (A) Expressions of BDNF and CRTC1 were examined by western blotting. (B) The expression of BDNF and CRTC1. Data were expressed as mean ± SD. ∗p < 0.05 and ∗∗p < 0.01 compared with the untreated control group. #p < 0.05 compared with its compound alone.
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Figure 4: Inhibitory effect of ERK1/2 and PI3K on DISS- or TFSA-induced BDNF and CRTC1 expressions in SY5Y cells (n = 9). SY5Y cells were pretreated with 10 μM U0126 or 30 μM LY294002 for 30 min, followed by treatment with 150 μM DISS or 50 μM TFSA for 48 h. (A) Expressions of BDNF and CRTC1 were examined by western blotting. (B) The expression of BDNF and CRTC1. Data were expressed as mean ± SD. ∗p < 0.05 and ∗∗p < 0.01 compared with the untreated control group. #p < 0.05 compared with its compound alone.
Mentions: Considering the various CREB pathways activated by DISS and TFSA, we assessed the signaling mechanisms involved in CRTC1 and BDNF regulation using two inhibitors. Figure 4 reveals that treatment of DISS or TFSA increased the expression of BDNF and CRTC1, but such an increase could be partially attenuated by either U0126 or LY294002. PI3-K inhibitor LY294003 showed a similar but weaker inhibitory effect on DISS-induced CRTC1 expression compared with U0126 (Figure 4A). The LY294002 decreased the DISS- or TFSA-induced BDNF expression by 47 and 25%, respectively. The ERK1/2 inhibitor U0126 decreased the DISS- or TFSA-induced BDNF expression by 25 and 21%, respectively. (Figure 4B). A bigger decrease in DISS- or TFSA-induced BDNF expression was caused by LY294003 compared with U0126 (Figure 4B).

View Article: PubMed Central - PubMed

ABSTRACT

As two natural oligosaccharide esters, 3,6&rsquo;-Disinapoyl sucrose (DISS) and tenuifolisideA (TFSA) are originating from the root of Polygala tenuifolia Willd, a traditional Chinese medicine used in treatment of mental disorders. Previous reports have shown that both of them possess in vitro neuroprotective effects by stimulating different upstream pathways related with cyclic AMP-responsive element-binding protein (CREB). In the present study, we investigated the additive neuroprotective effects of DISS and TFSA on Glu-induced damage of SY5Y cells and purposed the possible underlying mechanism. The interaction between DISS and TFSA showed a clear-cut synergistic effect as evidenced by combination index (CI). Additional evidence from biochemical (NOS activity) assays confirmed their additive inhibition on the Glu-induced NOS hyperactivation. Moreover, we showed that co-treatment of DISS and TFSA resulted in an additively up-regulated phosphorylation of CREB as well as increased expressions of CRTC1 and BDNF. Neuroprotective effects of DISS and TFSA on Glu-induced decrease in cell viability were blocked by MAPK/ERK1/2 inhibitor (U0126) and PI3-K inhibitor (LY290042). Nevertheless, the CRTC1 or BDNF expression induced by these two compounds was significantly reduced in the presence of either ERK or PI3-K inhibitor, indicating that the two oligosaccharide esters shared some common pathways in the regulation of CREB-BDNF pathway. Taken together, we, for the first time, showed that DISS and TFSA exerted the additive neuroprotective effects on CREB-BDNF signaling pathway through complementary mechanisms.

No MeSH data available.


Related in: MedlinePlus