Gracilins: Spongionella-derived promising compounds for Alzheimer disease

Marta Leirós; Eva Alonso; Mostafa E Rateb; Wael E Houssen; Rainer Ebel; Marcel Jaspars; Amparo Alfonso; Luis M Botana

doi:10.1016/j.neuropharm.2015.02.015

Gracilins: Spongionella-derived promising compounds for Alzheimer disease

Neuropharmacology. 2015 Jun:93:285-93. doi: 10.1016/j.neuropharm.2015.02.015. Epub 2015 Feb 24.

Authors

Marta Leirós¹, Eva Alonso¹, Mostafa E Rateb², Wael E Houssen³, Rainer Ebel⁴, Marcel Jaspars⁴, Amparo Alfonso¹, Luis M Botana⁵

Affiliations

¹ Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
² Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, UK; Pharmacognosy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 32514, Egypt.
³ Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, UK; Institute of Medical Sciences, University of Aberdeen, Ashgrove Road West, Aberdeen AB25 2ZD, Scotland, UK.
⁴ Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, UK.
⁵ Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain. Electronic address: Luis.Botana@usc.es.

PMID: 25724081
DOI: 10.1016/j.neuropharm.2015.02.015

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 ERK. 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-β42 and hyperphosphorylated tau levels were decreased after treatments and the ERK inhibition was also observed. This research highlights new bioactivities for gracilins, such as BACE1 and ERK inhibition, and provides more evidence for their potential therapeutic application in neurodegenerative diseases due to their multi-target activities, especially in AD.

Keywords: 3xTg-AD; Alzheimer disease; ERK; Gracilin; Morris water maze; Spongionella.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / genetics
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics
Animals
Antipsychotic Agents / chemistry
Antipsychotic Agents / therapeutic use*
Cell Line, Tumor
Disease Models, Animal
Diterpenes / therapeutic use*
Enzyme Inhibitors / pharmacology
Humans
Maze Learning / drug effects
Mice
Mice, Transgenic
Mutation / genetics
Neuroblastoma / pathology
Peptide Fragments / metabolism
Porifera / chemistry*
Presenilin-1 / genetics
Time Factors
tau Proteins / genetics

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Antipsychotic Agents
Diterpenes
Enzyme Inhibitors
Peptide Fragments
Presenilin-1
amyloid beta-protein (1-42)
tau Proteins
Amyloid Precursor Protein Secretases