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a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-β (Aβ) accumulation by affecting both Aβ production and Aβ clearance across the blood-brain barrier (BBB). PubMed:25331948

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a(CHEBI:Nilvadipine) directlyDecreases complex(GO:"L-type voltage-gated calcium channel complex") View Subject | View Object

We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain amyloid-β (Aβ) accumulation by affecting both Aβ production and Aβ clearance across the blood-brain barrier (BBB). PubMed:25331948

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 199)) View Subject | View Object

Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes PubMed:25331948

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes PubMed:25331948

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes PubMed:25331948

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes PubMed:25331948

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a(CHEBI:Nilvadipine) decreases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

Western blot analyses of brain homogenates show that (−)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes PubMed:25331948

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a(CHEBI:Nilvadipine) decreases p(HGNC:RAF1, pmod(Ph)) View Subject | View Object

In particular, we monitored RAF phosphorylation following treatment with (-)-nilvadipine and observed that (-)-nilvadipine prevents RAF phosphorylation induced by PMA (Fig. 4, C and D) suggesting that (-)-nilvadipine is impacting a target upstream of RAF PubMed:25331948

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Following 24 h of treatment with the pure enantiomers or the racemic mixture of nilvadipine, a dose-dependent inhibition of Aβ production was observed (Fig. 1A). PubMed:25331948

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

In addition, a reduction in BACE-1 protein levels was observed following treatment of HEK293 cells with (-)-nilvadipine or racemic nilvadipine (Fig. 1D) further suggesting that the inhibition of Aβ production observed following nilvadipine treatment is mediated in part by a reduction of BACE-1 expression. PubMed:25331948

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

We tested the effect of an acute treatment with (-)-nilvadipine or (+)-nilvadipine on brain Aβ levels using Tg PS1/APPsw mice, and we observed that both (-)-nilvadipine and (+)-nilvadipine acutely reduced brain Aβ levels with similar potency (Fig. 2, C and D). PubMed:25331948

a(CHEBI:Nilvadipine) decreases act(p(HGNC:APP)) View Subject | View Object

We have previously shown that racemic nilvadipine affects the β-cleavage of APP and reduces sAPPβ secretion PubMed:25331948

a(CHEBI:Nilvadipine) decreases sec(p(HBP:"sAPP-beta")) View Subject | View Object

We have previously shown that racemic nilvadipine affects the β-cleavage of APP and reduces sAPPβ secretion PubMed:25331948

a(CHEBI:Nilvadipine) decreases sec(p(HBP:"sAPP-beta")) View Subject | View Object

We found that, like (-)-nilvadipine, Syk inhibition with the selective Syk inhibitor BAY61-3606 resulted in decreased sAPPβ secretion, BACE-1 mRNA, and BACE-1 protein expression (data not shown). PubMed:25331948

a(CHEBI:Nilvadipine) decreases r(HGNC:BACE1) View Subject | View Object

We found that both (-)-nilvadipine and racemic nilvadipine reduce BACE-1 mRNA expression (Fig. 1C) induced by TNFα PubMed:25331948

a(CHEBI:Nilvadipine) decreases r(HGNC:BACE1) View Subject | View Object

We found that, like (-)-nilvadipine, Syk inhibition with the selective Syk inhibitor BAY61-3606 resulted in decreased sAPPβ secretion, BACE-1 mRNA, and BACE-1 protein expression (data not shown). PubMed:25331948

a(CHEBI:Nilvadipine) decreases p(HGNC:BACE1) View Subject | View Object

In addition, a reduction in BACE-1 protein levels was observed following treatment of HEK293 cells with (-)-nilvadipine or racemic nilvadipine (Fig. 1D) further suggesting that the inhibition of Aβ production observed following nilvadipine treatment is mediated in part by a reduction of BACE-1 expression. PubMed:25331948

a(CHEBI:Nilvadipine) decreases p(HGNC:BACE1) View Subject | View Object

As (-)-nilvadipine and racemic nilvadipine inhibit BACE-1 transcription, we evaluated whether (-)-nilvadipine was impacting NFkB activation because NFkB has been shown to play an important role in the regulation of BACE-1 transcription and expression (36, 37, 43, 44) PubMed:25331948

a(CHEBI:Nilvadipine) decreases p(HGNC:BACE1) View Subject | View Object

We found that, like (-)-nilvadipine, Syk inhibition with the selective Syk inhibitor BAY61-3606 resulted in decreased sAPPβ secretion, BACE-1 mRNA, and BACE-1 protein expression (data not shown). PubMed:25331948

a(CHEBI:Nilvadipine) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

We found that both the (-)- and (+)-nilvadipine enantiomers enhance Aβ42 clearance from the brain to the peripheral side of the in vitro BBB model (Fig. 2A). PubMed:25331948

a(CHEBI:Nilvadipine) increases tloc(a(CHEBI:"amyloid-beta polypeptide 42"), fromLoc(GO:intracellular), toLoc(MESH:Plasma)) View Subject | View Object

Data show that (-)-nilvadipine stimulated the clearance of human Aβ42 across the BBB as more human Aβ42 was detected in the plasma of (-)-nilvadipine-treated mice than control animals (Fig. 2B). PubMed:25331948

a(CHEBI:Nilvadipine) increases bp(GO:"amyloid-beta clearance by transcytosis") View Subject | View Object

We found that both the (-)- and (+)-nilvadipine enantiomers enhance Aβ42 clearance from the brain to the peripheral side of the in vitro BBB model (Fig. 2A). PubMed:25331948

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Ser, 199)) View Subject | View Object

Western blot analyses of brain homogenates show that (-)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes (Fig. 3). PubMed:25331948

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Ser, 202)) View Subject | View Object

Western blot analyses of brain homogenates show that (-)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes (Fig. 3). PubMed:25331948

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Thr, 205)) View Subject | View Object

Western blot analyses of brain homogenates show that (-)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes (Fig. 3). PubMed:25331948

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Ser, 396)) View Subject | View Object

Western blot analyses of brain homogenates show that (-)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes (Fig. 3). PubMed:25331948

a(CHEBI:Nilvadipine) decreases p(MGI:Mapt, pmod(Ph, Ser, 404)) View Subject | View Object

Western blot analyses of brain homogenates show that (-)-nilvadipine significantly reduces Tau phosphorylation in AT8 (phosphorylated Ser-199/Ser-202/Thr-205) and PHF-1 (phosphorylated Ser-396/Ser-404) epitopes (Fig. 3). PubMed:25331948

a(CHEBI:Nilvadipine) decreases act(p(HGNC:SYK)) View Subject | View Object

Using a cell-free assay using human recombinant Syk, we observed that (-)-nilvadipine dose-dependently inhibits Syk activity (Fig. 5A) PubMed:25331948

a(CHEBI:Nilvadipine) increases complex(a(CHEBI:Nilvadipine), p(HGNC:SYK)) View Subject | View Object

To ensure that the reduction in Syk activity observed was not due to an interaction of the peptide substrate with (-)-nilvadipine, we also verified that (-)-nilvadipine was able to directly bind to Syk. PubMed:25331948

a(CHEBI:Nilvadipine) increases complex(a(CHEBI:Nilvadipine), p(HGNC:SYK)) View Subject | View Object

We measured the binding affinity of (-)-nilvadipine for Syk using biolayer interferometry and confirmed that (-)-nilvadipine binds to human recombinant Syk with a binding dissociation constant (KD) of 2.1 µM (Fig. 5C), further suggesting that Syk is the possible target impacted by nilvadipine. PubMed:25331948

a(CHEBI:Nilvadipine) decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

The magnitude of the NFkB inhibition following (-)-nilvadipine treatment was also reduced in clones of HEK293 NFkB luciferase reporter cells in which Syk expression had been silenced (data not shown) further suggesting that Syk is required to mediate the inhibition of NFkB activity induced by (-)-nilvadipine. PubMed:25331948

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BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.