Gracilins: Spongionella-derived promising compounds for Alzheimer disease.
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.
Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
Marta
M
Leirós
Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
Eva
E
Alonso
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.
Mostafa E
ME
Rateb
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.
Wael E
WE
Houssen
Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, UK.
Rainer
R
Ebel
Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, Scotland, UK.
Marcel
M
Jaspars
Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
Amparo
A
Alfonso
Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain. Electronic address: Luis.Botana@usc.es.
Luis M
LM
Botana
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004224:Diterpenes / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D011161:Porifera / Q000737:chemistry*; D053764:Presenilin-1 / Q000235:genetics; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D004224:Diterpenes; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases
3xTg-AD; Alzheimer disease; ERK; Gracilin; Morris water maze; Spongionella