Influence of Selected Natural Products on Neutral Endopeptidase Activity and β-Amyloid Production in SK-N-SH Cells

Ayoub, Shereen; Melzig, Matthias F.

doi:10.1080/13880200802055891

Cited by 8 publications

(9 citation statements)

References 44 publications

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“…Previously, somatostatin, rolipram, luteolin, apigenin, and curcumin was reported showing the ability of increasing NEP activity using activity assay but there was no supporting data showing increase in NEP mRNA or protein levels 16 40 . Using activity assay alone could not exclude the possibility the substrate degradation coming from the action of other proteases.…”

Section: Discussionmentioning

confidence: 96%

“…Certain medicinal plants are thought to be effective in improving brain function, and secondary metabolites in plants have been extensively examined as possible AD therapeutic reagents. Ayoub and Melzig found that apigenin, luteolin, and curcumin increased both ACE and NEP activity and rolipram increased only NEP activity in human SK-N-SH neuroblastoma cells 16 . Eisele et al .…”

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confidence: 99%

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Polyhydroxycurcuminoids but not curcumin upregulate neprilysin and can be applied to the prevention of Alzheimer’s disease

Chen

Chen²,

Hou

et al. 2016

Sci Rep

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Neprilysin (NEP) is the most important Aβ-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer’s disease. Recently, many reports showed that upregulating NEP level is a promising strategy in the prevention and therapy of Alzheimer’s disease. Here, we used a sensitive fluorescence-based Aβ digestion assay to screen 25 curcumin analogs for their ability to upregulate NEP activity. To our surprise, four compounds, dihydroxylated curcumin, monohydroxylated demethoxycurcumin, and mono- and di-hydroxylated bisdemethoxycurcumin, increased NEP activity, while curcumin did not. The ability of these polyhydroxycurcuminoids to upregulate NEP was further confirmed by mRNA and protein expression levels in the cell and mouse models. Finally, feeding monohydroxylated demethoxycurcumin (also named demethylcurcumin) or dihydroxylated bisdemethoxycurcumin (also named bisdemethylcurcumin) to APPswe/PS1dE9 double transgenic mice upregulated NEP levels in the brain and reduced Aβ accumulation in the hippocampus and cortex. These polyhydroxycurcuminoids offer hope in the prevention of Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Polyhydroxycurcuminoids but not curcumin upregulate neprilysin and can be applied to the prevention of Alzheimer’s disease

Chen

Chen²,

Hou

et al. 2016

Sci Rep

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“…For instance, Saito et al [ 22 ] used a concentration of glutaryl-Ala-Ala-Phe-methoxy-2-naphthylamide (Sigma) of 500 μM and this peptide substrate could be digested by many other proteases [ 23 ]. SAAP-AMC (Suc-L-Ala-L-Ala-L-Phe-7-amido-3-methylcoumarin, Sigma) [ 25 , 26 ] was used to screen natural compounds that could increase NEP activity in the neuroblastoma SK-N-SH cells. The substrate concentration was 44 μM and a subsequent digestion step by aminopeptidase N was required.…”

Section: Resultsmentioning

confidence: 99%

Design of Peptide Substrate for Sensitively and Specifically Detecting Two Aβ-Degrading Enzymes: Neprilysin and Angiotensin-Converting Enzyme

Chen

Lin

et al. 2016

PLoS ONE

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Upregulation of neprilysin (NEP) to reduce Aβ accumulation in the brain is a promising strategy for the prevention of Alzheimer’s disease (AD). This report describes the design and synthesis of a quenched fluorogenic peptide substrate qf-Aβ(12–16)AAC (with the sequence ), which has a fluorophore, Alexa-350, linked to the side-chain of its C-terminal cysteine and a quencher, Dabcyl, linked to its N-terminus. This peptide emitted strong fluorescence upon cleavage. Our results showed that qf-Aβ(12–16)AAC is more sensitive to NEP than the previously reported peptide substrates, so that concentrations of NEP as low as 0.03 nM could be detected at peptide concentration of 2 μM. Moreover, qf-Aβ(12–16)AAC had superior enzymatic specificity for both NEP and angiotensin-converting enzyme (ACE), but was inert with other Aβ-degrading enzymes. This peptide, used in conjunction with a previously reported peptide substrate qf-Aβ(1–7)C [which is sensitive to NEP and insulin-degrading enzyme (IDE)], could be used for high-throughput screening of compounds that only upregulate NEP. The experimental results of cell-based activity assays using both qf-Aβ(1–7)C and qf-Aβ(12–16)AAC as the substrates confirm that somatostatin treatment most likely upregulates IDE, but not NEP, in neuroblastoma cells.

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“…Referring to the studies searching for agents that may up-regulate NEP gene expression; enhancing its activity and promoting its action (Borson, 1991), a variety of selective enhancers are pre-clinically developed involving drugs (glucocorticoids) (Borson and Gruenert, 1991), hormones (androgens (Yao et al, 2008) and estrogen (Xiao et al, 2009)) or natural products (Apigenin, Luteolin, and Curcumin, (-)-Epigallocatechin-3-gallate and Resveratrol) (Ayoub and Melzig, 2008;Chang et al, 2015;El-Sayed and Bayan, 2015).…”

Section: Potential Covid-19 Therapiesmentioning

confidence: 99%

“…Along with, Rolipram, an investigative PDE4i, has also been examined; suggesting that increasing the levels of intracellular cAMP was directly correlated with enhanced NEP activity, which in turn may prolong and potentiate the cAMP-mediated short-term anti-inflammatory mechanism (Graf et al, 1995;Ayoub and Melzig, 2008).…”

Section: Potential Covid-19 Therapiesmentioning

confidence: 99%

New putative insights into Neprilysin (NEP)-dependent pharmacotherapeutic role of Roflumilast in treating COVID-19

Tabaa

2020

Preprint

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Nowadays, COVID-19 represents the most serious inflammatory respiratory disease worldwide. Despite of many proposed therapies, no effective medication has been approved yet. Neutrophils appear to be the key mediator for COVID-19-associated inflammatory immunopathologic, thromboembolic and fibrotic complications. Thus, for any therapeutic agent to be more appropriate, it should greatly block the neutrophilic component of COVID-19. One of the effective therapeutic approaches investigated to reduce neutrophils-associated inflammatory lung diseases with less adverse effects was Roflumilast. Being a highly selective PDE4i, roflumilast acts by enhancing cAMP level, that probably potentiates its anti-inflammatory action via increasing NEP activity. Because activating NEP was previously reported to mitigate several airway inflammatory ailments; this review deeply discusses the proposed NEP-based therapeutic properties of roflumilast, which may be of great importance in curing COVID-19. However, further clinical studies are required to confirm this strategy and to evaluate its in-vivo preventive and therapeutic efficacy against COVID-19.

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Influence of Selected Natural Products on Neutral Endopeptidase Activity and β-Amyloid Production in SK-N-SH Cells

Cited by 8 publications

References 44 publications

Polyhydroxycurcuminoids but not curcumin upregulate neprilysin and can be applied to the prevention of Alzheimer’s disease

Polyhydroxycurcuminoids but not curcumin upregulate neprilysin and can be applied to the prevention of Alzheimer’s disease

Design of Peptide Substrate for Sensitively and Specifically Detecting Two Aβ-Degrading Enzymes: Neprilysin and Angiotensin-Converting Enzyme

New putative insights into Neprilysin (NEP)-dependent pharmacotherapeutic role of Roflumilast in treating COVID-19

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