Identification of naturally occurring spirostenols preventing β-amyloid-induced neurotoxicity

Lecanu, Laurent; Yao, Wenguo; Teper, Gary; Yao, Zhixing; Greeson, Janet; Papadopoulos, Vassilios

doi:10.1016/j.steroids.2003.09.007

Cited by 48 publications

(46 citation statements)

References 51 publications

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“…We present herein results reporting that procaine and other local anesthetics exhibit interesting neuroprotective properties against Aß 1-42 neurotoxicity suggesting that these small molecules might be useful to treat AD in association, or not, with current drugs. Aß 1-42 induced a dose-dependent decrease of the PC12 cell viability which was accompanied by decrease of the intracellular ATP concentrations, confirming data previously reported by others and us on neuronal cells [17,23,24]. All the different compounds studied displayed neuroprotective properties, although some differences of efficacy were observed.…”

Section: Discussionsupporting

confidence: 89%

“…The cellular toxicity of Aß was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay (Trevigen, Gaithersburg, Md., USA) as previously described [17]. Briefly, 10 Ìl of the MTT solution was added to the cells cultured in 100 Ìl of medium.…”

Section: Cell Viability Determinationmentioning

confidence: 99%

“…ATP concentrations were measured using the ATPLite-M TM assay (Packard BioSciences Co.), as previously described [17]. In brief, cells were cultured on black 96-well ViewPlate TM and the ATP concentrations measured on a TopCount NXT TM counter (Packard BioSciences Co.) according to the manufacturer's recommendations.…”

Section: Atp Measurementmentioning

confidence: 99%

“…Oxidative stress was assessed by measuring the free radical production using the fluorescent probe di-hydroxy di-chlorofluorescein diacetate (2,7-DCF) (Molecular Probes, Eugene, Oreg., USA), as previously described [17]. For these experiments, cells were cultured in polylysine-coated microplates.…”

Section: Free Radical Productionmentioning

confidence: 99%

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Local Anesthetic Procaine Protects Rat Pheochromocytoma PC12 Cells against β-Amyloid-Induced Neurotoxicity

Lecanu

Yao

et al. 2005

Pharmacology

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Alzheimer’s disease (AD) is the most common dementia occurring in elderly. We report herein the neuroprotective properties of procaine and other anesthetic agents against β-amyloid-induced neurotoxicity. Procaine displayed strong neuroprotective properties against the amyloid peptide Aβ_1–42 and preserved Aβ_1–42-induced ATP depletion on rat pheochromocytoma PC12 cells. Procaine also inhibited the neurotoxic effect that glutamate displayed on PC12 cells, suggesting that the reduction of glutamate-induced neurotoxicity may be the mechanism by which these compounds exert their ‘antiamyloid’ effects. In search of a mechanism of action we observed that procaine is a ligand for the σ1 receptor, a protein which ligands have been shown to protect mitochondrial function and to exert antidepressant properties. Procaine binds also to muscarinic receptors but the true meaning of this feature needs to be clarified. In conclusion, these data suggest that procaine exerts neuroprotective properties and may serve either as a treatment for AD or as a starting point for the development of novel therapies for AD.

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Section: Discussionsupporting

confidence: 89%

Section: Cell Viability Determinationmentioning

confidence: 99%

Section: Atp Measurementmentioning

confidence: 99%

Section: Free Radical Productionmentioning

confidence: 99%

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Local Anesthetic Procaine Protects Rat Pheochromocytoma PC12 Cells against β-Amyloid-Induced Neurotoxicity

Lecanu

Yao

et al. 2005

Pharmacology

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“…Although neurotoxic [45,46] , ADDLs did not induce neuronal death in the rat brains infused with A ␤ 42 alone, or in combination only with Fe 2+ , suggesting that the oxidative stress generated by the FAB solution made the rat brain vulnerable to the neurotoxic effects of the amyloid oligomers.…”

Section: Discussionmentioning

confidence: 90%

Beta-Amyloid and Oxidative Stress Jointly Induce Neuronal Death, Amyloid Deposits, Gliosis, and Memory Impairment in the Rat Brain

Lecanu

Greeson²,

Papadopoulos³

2005

Pharmacology

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Infusion of Fe²⁺, Aβ₄₂, and buthionine-sulfoximine (FAB), but not Aβ₄₂ alone or in combination with Fe²⁺, into the left cerebral ventricle of Long-Evans rats for 4 weeks induced memory impairment that was accompanied by increased hyperphosphorylated Tau protein levels in the CSF. FAB-infused animals displayed thioflavin-S-positive amyloid deposits, hyperphosphorylated Tau protein, neuronal loss, and gliosis. Animals treated with Aβ₄₂, Fe²⁺, or buthionine-sulfoximine alone or in combination failed to show the histological modifications seen with FAB. This data suggests that Aβ₄₂ is not sufficient to induce an Alzheimer’s disease-like symptomatology, and it supports a model whereby a decrease in the brain’s antioxidant defense system leads to the Aβ₄₂-independent oxidative stress necessary for the peptide to induce histopathological changes and memory loss.

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Entwicklung von Inhibitoren der Tau‐Aggregation bei Morbus Alzheimer

et al. 2009

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Mit kleinen Molekülen gegen Alzheimer: Die pathologische Aggregation des Tau‐Proteins ist ein Hauptmerkmal bei neurodegenerativen Erkrankungen wie der Alzheimerkrankheit und anderen Tauopathien. Die Inhibierung oder gar die Umkehr der Tau‐Aggregation sind potenzielle therapeutische Strategien, die sich derzeit in der klinischen Prüfung befinden. Das Bild zeigt charakteristische pathologische Fibrillen aus Tau‐Proteinen (paarige helikale Filamente), die die Hauptkomponente der bei Alzheimer auftretenden neurofibrillären Bündel sind. Eine Vielzahl humaner Erkrankungen steht vermutlich in direkter Verbindung mit der Fehlfaltung von Proteinen. Hierbei werden typischerweise hochorganisierte Proteinaggregate, so genannte Amyloidfibrillen, sowie deren Aggregationsintermediate beobachtet. Diese gelten allgemein als Vermittler der Zytotoxizität und stehen demzufolge im Fokus der Forschung. Die pathologische Aggregation des Tau‐Proteins ist ein Hauptmerkmal einiger neurodegenerativer Erkrankungen wie der Alzheimerkrankheit. Im vergangenen Jahrzehnt hat man sich daher verstärkt der Suche nach Inhibitoren der Tau‐Aggregation als potenzielle krankheitsmodifizierende Wirkstoffe bei Morbus Alzheimer und anderen “Tauopathien” gewidmet. Der jüngste Bericht einer klinischen Phase‐II‐Studie des Tau‐Aggregationsinhibitors MTC stellt eine Validierung des Konzepts in Aussicht. In diesem Aufsatz fassen wir die verfügbaren Daten über niedermolekulare Inhibitoren der Tau‐Aggregation von einem medizinisch‐chemischen Standpunkt heraus zusammen.

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Identification of naturally occurring spirostenols preventing β-amyloid-induced neurotoxicity

Cited by 48 publications

References 51 publications

Local Anesthetic Procaine Protects Rat Pheochromocytoma PC12 Cells against β-Amyloid-Induced Neurotoxicity

Local Anesthetic Procaine Protects Rat Pheochromocytoma PC12 Cells against β-Amyloid-Induced Neurotoxicity

Beta-Amyloid and Oxidative Stress Jointly Induce Neuronal Death, Amyloid Deposits, Gliosis, and Memory Impairment in the Rat Brain

Entwicklung von Inhibitoren der Tau‐Aggregation bei Morbus Alzheimer

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