In Vitro Effects of Serotonin, Melatonin, and Other Related Indole Compounds on Amyloid‐β Kinetics and Neuroprotection

Hornedo-Ortega, Ruth; Costa, Grégory Da; Cerezo, Ana B.; Troncoso, Ana M.; Richard, Tristan; García-Parrilla, M.C.

doi:10.1002/mnfr.201700383

Cited by 43 publications

(27 citation statements)

References 62 publications

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“…In addition, tryptophan showed an age-related decrease in both AD and Ctrl groups, and significant correlations with γ-GT, ALT, and FT4 in our study, which suggested that tryptophan may be a clinical marker of disease risk in the elderly. Recently, an in vitro study showed that tryptophan, serotonin, melatonin, and other indole compounds, protected against Aβ peptide aggregation and cytotoxicity [ 39 ]. Investigation of the possible mechanism underlying the neuroprotective effects of indole compounds may result in identification of novel potential therapeutic targets for AD.…”

Section: Discussionmentioning

confidence: 99%

Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer’s Disease

Shao¹,

Ouyang²,

Li³

et al. 2020

Aging and disease

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The expending of elderly population worldwide has resulted in a dramatic rise in the incidence of chronic diseases such as Alzheimer's disease (AD). Inadequate understanding of the mechanisms underlying AD has hampered the development of efficient tools for definitive diagnosis and curative interventions. Previous studies have attempted to discover reliable biomarkers of AD, but these biomarkers can only be measured through invasive (neuropathological markers in cerebrospinal fluid) or expensive (positron emission tomography scanning or magnetic resonance imaging) techniques. Metabolomics is a high-throughput technology that can detect and catalog large numbers of small metabolites and may be a useful tool for characterization of AD and identification of biomarkers. In this study, we used ultra-performance liquid chromatography-mass spectrometry based untargeted metabolomics to measure the concentrations of plasma metabolites in a cohort of subjects with AD (n=44) and cognitively normal controls (Ctrl, n=94). The AD group showed marked reductions in levels of polyunsaturated fatty acids, acyl-carnitines, degradation products of tryptophan, and elevated levels of bile acids compared to the Ctrl group. We then validated the results using an independent cohort that included subjects with AD (n=30), mild cognitive impairment (MCI, n=13), healthy controls (n=43), and non-AD neurological disease controls (NDC, n=31). We identified five metabolites comprising cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid, and tryptophan that were able to distinguish patients with AD from both Ctrl and NDC with satisfactory sensitivity and specificity. The concentrations of these metabolites were significantly correlated with disease severity. Our results also suggested that altered bile acid profiles in AD and MCI might indicate early risk for the development of AD. These findings may allow for development of new approaches for diagnosis of AD and may provide novel insights into AD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer’s Disease

Shao¹,

Ouyang²,

Li³

et al. 2020

Aging and disease

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“…Indeed, it has proved to significantly inhibit VEGF-induced VEGFR-2 activation in human umbilical vein endothelial cells which is known to trigger subsequent angiogenesis [46] that is related to CVD and cancer. Moreover, Melatonin as well as certain related indolic compounds, mainly serotonin, show an inhibitory and destabilizing effect on amyloid-β peptide fibril formation as recently reported [47] showing neuroprotective properties. Likewise, Ono et al reported recently that MEL inhibits α-Syn assembly [48]; on the other hand, there are some studies that reveal that MEL is able to cross the BBB [49,50]; these data suggest that MEL strongly inhibits the protofibril formation.…”

Section: Introductionmentioning

confidence: 69%

“…A substantial body of evidence suggests that MEL may inhibits the fibril formation of some amyloidogenic proteins (β-amyloid peptide and tau, α-Syn) [47,48]. MEL was able to attenuate arsenite-induced apoptosis via a reduction of aggregated α-Syn levels in rat brain [79] by Western blot analysis.…”

Section: Discussionmentioning

confidence: 97%

Simultaneous Occurrence of Bioactive Compounds (Melatonin, Protocatechuic Acid and Hydroxytyrosol) Increases Their Neuroprotective Effects Against Alpha-Synuclein-Induced Proteotoxicity

Gallardo-Fernández¹,

Hornedo-Ortega²,

Cerezo³

et al. 2018

Preprint

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The abnormal assembly of α-synuclein (α-Syn) is an initial step in the formation of Lewy bodies in the brain, which finally causes the neuronal death, being considered as a pathological hallmark in Parkinson’s disease (PD). Certain food bioactives or their metabolites at very low concentrations can trespass the blood brain barrier (BBB) that might, thereafter, act simultaneously. The aim of this work was to evaluate the inhibitory and destabilising capacities on α-Syn kinetics and the neuroprotective effects of three well-known bioactive compounds able to cross the BBB and present in foods; melatonin (MEL), protocatechuic acid (PCA) and hydroxytyrosol (HT), and their combinations. For this purpose, different in vitro techniques (Thioflavin T (ThT), Transmission Electronic Microscopy (TEM), electrophoresis and MTT assay) were used. All tested compounds and their combinations were able to abolish the toxicity induced by α-Syn. In addition, the combination of PCA (100 µM) +HT (100 µM) showed the highest inhibitory effect against α-Syn fibril formation and destabilises α-Syn fibrils (88 and 62%, respectively). This is the first time that MEL, PCA and HT prove a joint effect against α-Syn aggregation and toxicity when they are tested together.

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“…Figure 3. These three compounds inhibit in vitro amyloid-β peptide fibril formation [38][39][40], while the others do not have any known effect on prion or fibril formation. Thus, the effects seen in the ShIC-RENAGE assay are not generic effects arising from anti-amyloid compounds (polyphenols and aromatics).…”

Section: Effect Of Anti-prion Fibril Small Molecules On Prp Shicmentioning

confidence: 95%

A simple in vitro assay for assessing the efficacy, mechanisms and kinetics of anti-prion fibril compounds

Ladner-Keay

Ross

Perez-Pineiro

et al. 2018

Prion

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Prion diseases are caused by the conversion of normal cellular prion proteins (PrP) into lethal prion aggregates. These prion aggregates are composed of proteinase K (PK) resistant fibrils and comparatively PK-sensitive oligomers. Currently there are no anti-prion pharmaceuticals available to treat or prevent prion disease. Methods of discovering anti-prion molecules rely primarily on relatively complex cell-based, tissue slice or animal-model assays that measure the effects of small molecules on the formation of PK-resistant prion fibrils. These assays are difficult to perform and do not detect the compounds that directly inhibit oligomer formation or alter prion conversion kinetics. We have developed a simple cell-free method to characterize the impact of anti-prion fibril compounds on both the oligomer and fibril formation. In particular, this assay uses shaking-induced conversion (ShIC) of recombinant PrP in a 96-well format and resolution enhanced native acidic gel electrophoresis (RENAGE) to generate, assess and detect PrP fibrils in a high throughput fashion. The end-point PrP fibrils from this assay can be further characterized by PK analysis and negative stain transmission electron microscopy (TEM). This cell-free, gel-based assay generates metrics to assess anti-prion fibril efficacy and kinetics. To demonstrate its utility, we characterized the action of seven well-known anti-prion molecules: Congo red, curcumin, GN8, quinacrine, chloropromazine, tetracycline, and TUDCA (taurourspdeoxycholic acid), as well as four suspected anti-prion compounds: trans-resveratrol, rosmarinic acid, myricetin and ferulic acid. These findings suggest that this in vitro assay could be useful in identifying and comprehensively assessing novel anti-prion fibril compounds. Abbreviations: PrP, prion protein; PK, proteinase K; ShIC, shaking-induced conversion; RENAGE, resolution enhanced native acidic gel electrophoresis; TEM, transmission electron microscopy; TUDCA, taurourspdeoxycholic acid; BSE, bovine spongiform encephalopathy; CWD, chronic wasting disease; CJD, Creutzfeldt Jakob disease; GSS, Gerstmann-Sträussler-Scheinker syndrome; FFI, fatal familial insomnia; PrP, cellular prion protein; recPrP, recombinant monomeric prion protein; PrP, infectious particle of misfolded prion protein; RT-QuIC, real-time quaking-induced conversion; PMCA, Protein Misfolding Cyclic Amplification; LPS, lipopolysaccharide; EGCG, epigallocatechin gallate; GN8, 2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide; DMSO, dimethyl sulfoxide; ScN2A, scrapie infected neuroblastoma cells; IC50, inhibitory concentration for 50% reduction; recMoPrP , recombinant full-length mouse prion protein residues 23-231; EDTA; PICUP, photo-induced cross-linking of unmodified protein; BSA, bovine serum albumin;; PMSF, phenylmethanesulfonyl fluoride.

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In Vitro Effects of Serotonin, Melatonin, and Other Related Indole Compounds on Amyloid‐β Kinetics and Neuroprotection

Abstract: Melatonin and other related indolic compounds, mainly serotonin, show an inhibitory and destabilizing effect on amyloid-β peptide fibril formation and they possess neuroprotective properties related to the vitagenes system.

Cited by 43 publications

References 62 publications

Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer’s Disease

Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer’s Disease

Simultaneous Occurrence of Bioactive Compounds (Melatonin, Protocatechuic Acid and Hydroxytyrosol) Increases Their Neuroprotective Effects Against Alpha-Synuclein-Induced Proteotoxicity

A simple in vitro assay for assessing the efficacy, mechanisms and kinetics of anti-prion fibril compounds

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