Gracilins

Spongionella-derived promising compounds for Alzheimer disease

Marta Leiros, Eva Alonso, Mostafa E. Rateb, Wael E. Houssen, Rainer Peter Ebel, Marcel Jaspars, Amparo Alfonso, Luis M. Botana*

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Alzheimer disease (AD) is a neurodegenerative pathology that is strongly linked with oxidative stress and mitochondrial dysfunction. The unclear origin of AD lead researchers to study several drug targets and it has been proposed that a multi-target drug would be a more promising candidate. Gracilins are sponge-derived diterpenoid compounds that have been described to act as antioxidants through mitochondrial targeting and through the induction of Nrf2 translocation. In this work gracilin H, A and L and tetrahydroaplysulphurin-1 have been studied in two neuroblastoma cellular models. First the BE(2)-M17 cell line has been used as a model for APP metabolism studies and next, SH-SY5Y-TMHT441 cells were used for AD drugs screening targeting tau phosphorylation. In vitro assays showed that gracilins were able to inhibit BACE1, reduce tau hyperphosphorylation and inhibit ERIC These positive results lead us to test gracilin H and L in 3xTg-AD mice. After chronic intraperitoneal treatments, a preliminary behavioral test pointed a positive trend on learning and spatial memory of mice treated with these compounds. Moreover in vivo assays confirmed the previous results. Amyloid-beta 42 and hyperphosphorylated tau levels were decreased after treatments and the ERIC inhibition was also observed. This research highlights new bioactivities for gracilins, such as BACE1 and ERIC inhibition, and provides more evidence for their potential therapeutic application in neurodegenerative diseases due to their multi-target activities, especially in AD. (C) 2015 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)285-293
Number of pages9
JournalNeuropharmacology
Volume93
Early online date24 Feb 2015
DOIs
Publication statusPublished - Jun 2015

Keywords

  • Gracilin
  • Spongionella
  • Alzheimer disease
  • ERK
  • 3xTg-AD
  • Morris water maze
  • marine natural-products
  • miscellaneous mechanisms
  • antiviral activities
  • nervous systems
  • oxidative stress
  • secondary metabolites
  • cellular-model
  • TAU-protein
  • antibacterial
  • pharmacology

Cite this

Gracilins : Spongionella-derived promising compounds for Alzheimer disease. / Leiros, Marta; Alonso, Eva; Rateb, Mostafa E.; Houssen, Wael E.; Ebel, Rainer Peter; Jaspars, Marcel; Alfonso, Amparo; Botana, Luis M.

In: Neuropharmacology, Vol. 93, 06.2015, p. 285-293.

Research output: Contribution to journalArticle

@article{52b26704647b498789e7336198088859,
title = "Gracilins: Spongionella-derived promising compounds for Alzheimer disease",
abstract = "Alzheimer disease (AD) is a neurodegenerative pathology that is strongly linked with oxidative stress and mitochondrial dysfunction. The unclear origin of AD lead researchers to study several drug targets and it has been proposed that a multi-target drug would be a more promising candidate. Gracilins are sponge-derived diterpenoid compounds that have been described to act as antioxidants through mitochondrial targeting and through the induction of Nrf2 translocation. In this work gracilin H, A and L and tetrahydroaplysulphurin-1 have been studied in two neuroblastoma cellular models. First the BE(2)-M17 cell line has been used as a model for APP metabolism studies and next, SH-SY5Y-TMHT441 cells were used for AD drugs screening targeting tau phosphorylation. In vitro assays showed that gracilins were able to inhibit BACE1, reduce tau hyperphosphorylation and inhibit ERIC These positive results lead us to test gracilin H and L in 3xTg-AD mice. After chronic intraperitoneal treatments, a preliminary behavioral test pointed a positive trend on learning and spatial memory of mice treated with these compounds. Moreover in vivo assays confirmed the previous results. Amyloid-beta 42 and hyperphosphorylated tau levels were decreased after treatments and the ERIC inhibition was also observed. This research highlights new bioactivities for gracilins, such as BACE1 and ERIC inhibition, and provides more evidence for their potential therapeutic application in neurodegenerative diseases due to their multi-target activities, especially in AD. (C) 2015 Elsevier Ltd. All rights reserved.",
keywords = "Gracilin, Spongionella, Alzheimer disease, ERK, 3xTg-AD, Morris water maze, marine natural-products, miscellaneous mechanisms, antiviral activities, nervous systems, oxidative stress, secondary metabolites, cellular-model, TAU-protein, antibacterial, pharmacology",
author = "Marta Leiros and Eva Alonso and Rateb, {Mostafa E.} and Houssen, {Wael E.} and Ebel, {Rainer Peter} and Marcel Jaspars and Amparo Alfonso and Botana, {Luis M.}",
note = "Acknowledgments From the European Union's Seventh Framework Program managed by REA – Research Executive Agency (FP7/2007-2013) under grant agreement Nos. 265409 μAQUA, 315285 CIGUATOOLS and 312184 PHARMASEA. We acknowledge the contribution of the National Cancer Institute via its Open Repository Programme for provision of the original Spongionella extracts. The Scottish University Life Science Alliance is acknowledged for their funding of the Marine Biodiscovery Centre Compound Library. We thank Dr. Gim{\'e}nez-Llort (Universidad Autonoma de Barcelona) and Dr. Laferla (University of California, Irvine) for their collaboration providing the 3xTg-AD mice.",
year = "2015",
month = "6",
doi = "10.1016/j.neuropharm.2015.02.015",
language = "English",
volume = "93",
pages = "285--293",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "PERGAMON-ELSEVIER SCIENCE LTD",

}

TY - JOUR

T1 - Gracilins

T2 - Spongionella-derived promising compounds for Alzheimer disease

AU - Leiros, Marta

AU - Alonso, Eva

AU - Rateb, Mostafa E.

AU - Houssen, Wael E.

AU - Ebel, Rainer Peter

AU - Jaspars, Marcel

AU - Alfonso, Amparo

AU - Botana, Luis M.

N1 - Acknowledgments From the European Union's Seventh Framework Program managed by REA – Research Executive Agency (FP7/2007-2013) under grant agreement Nos. 265409 μAQUA, 315285 CIGUATOOLS and 312184 PHARMASEA. We acknowledge the contribution of the National Cancer Institute via its Open Repository Programme for provision of the original Spongionella extracts. The Scottish University Life Science Alliance is acknowledged for their funding of the Marine Biodiscovery Centre Compound Library. We thank Dr. Giménez-Llort (Universidad Autonoma de Barcelona) and Dr. Laferla (University of California, Irvine) for their collaboration providing the 3xTg-AD mice.

PY - 2015/6

Y1 - 2015/6

N2 - Alzheimer disease (AD) is a neurodegenerative pathology that is strongly linked with oxidative stress and mitochondrial dysfunction. The unclear origin of AD lead researchers to study several drug targets and it has been proposed that a multi-target drug would be a more promising candidate. Gracilins are sponge-derived diterpenoid compounds that have been described to act as antioxidants through mitochondrial targeting and through the induction of Nrf2 translocation. In this work gracilin H, A and L and tetrahydroaplysulphurin-1 have been studied in two neuroblastoma cellular models. First the BE(2)-M17 cell line has been used as a model for APP metabolism studies and next, SH-SY5Y-TMHT441 cells were used for AD drugs screening targeting tau phosphorylation. In vitro assays showed that gracilins were able to inhibit BACE1, reduce tau hyperphosphorylation and inhibit ERIC These positive results lead us to test gracilin H and L in 3xTg-AD mice. After chronic intraperitoneal treatments, a preliminary behavioral test pointed a positive trend on learning and spatial memory of mice treated with these compounds. Moreover in vivo assays confirmed the previous results. Amyloid-beta 42 and hyperphosphorylated tau levels were decreased after treatments and the ERIC inhibition was also observed. This research highlights new bioactivities for gracilins, such as BACE1 and ERIC inhibition, and provides more evidence for their potential therapeutic application in neurodegenerative diseases due to their multi-target activities, especially in AD. (C) 2015 Elsevier Ltd. All rights reserved.

AB - Alzheimer disease (AD) is a neurodegenerative pathology that is strongly linked with oxidative stress and mitochondrial dysfunction. The unclear origin of AD lead researchers to study several drug targets and it has been proposed that a multi-target drug would be a more promising candidate. Gracilins are sponge-derived diterpenoid compounds that have been described to act as antioxidants through mitochondrial targeting and through the induction of Nrf2 translocation. In this work gracilin H, A and L and tetrahydroaplysulphurin-1 have been studied in two neuroblastoma cellular models. First the BE(2)-M17 cell line has been used as a model for APP metabolism studies and next, SH-SY5Y-TMHT441 cells were used for AD drugs screening targeting tau phosphorylation. In vitro assays showed that gracilins were able to inhibit BACE1, reduce tau hyperphosphorylation and inhibit ERIC These positive results lead us to test gracilin H and L in 3xTg-AD mice. After chronic intraperitoneal treatments, a preliminary behavioral test pointed a positive trend on learning and spatial memory of mice treated with these compounds. Moreover in vivo assays confirmed the previous results. Amyloid-beta 42 and hyperphosphorylated tau levels were decreased after treatments and the ERIC inhibition was also observed. This research highlights new bioactivities for gracilins, such as BACE1 and ERIC inhibition, and provides more evidence for their potential therapeutic application in neurodegenerative diseases due to their multi-target activities, especially in AD. (C) 2015 Elsevier Ltd. All rights reserved.

KW - Gracilin

KW - Spongionella

KW - Alzheimer disease

KW - ERK

KW - 3xTg-AD

KW - Morris water maze

KW - marine natural-products

KW - miscellaneous mechanisms

KW - antiviral activities

KW - nervous systems

KW - oxidative stress

KW - secondary metabolites

KW - cellular-model

KW - TAU-protein

KW - antibacterial

KW - pharmacology

U2 - 10.1016/j.neuropharm.2015.02.015

DO - 10.1016/j.neuropharm.2015.02.015

M3 - Article

VL - 93

SP - 285

EP - 293

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -