title: In vitro neuroprotective potential of lichen metabolite fumarprotocetraric acid via intracellular redox modulation.
abstract: The lichen-forming fungi Cetraria islandica has been largely used in folk medicines, and it has recently showed promising in vitro antioxidant effects in glial-like cells. Current work aimed at investigating the neuroprotective potential of its major isolated secondary metabolite: the depsidone fumarprotocetraric acid (FUM). H2O2was used herein to induce oxidative stress (OS)-mediated cytotoxicity in two models of neurons and astrocytes cells (SH-SY5Y and U373-MG cell lines). We found that a pre-treatment with FUM significantly enhanced cell viability compared to H2O2-treated cells, and we selected the optimal concentrations in each model (1 and 25μg/ml, respectively) for assessing its cytoprotective mechanisms. FUM, which exerted effective peroxyl radical scavenging effect in the chemical oxygen radical antioxidant capacity (ORAC) assay, alleviated the alterations in OS markers provoked by H2O2. It attenuated intracellular ROS formation, lipid peroxidation and GSH depletion. At mitochondrial level, FUM prevented from the dissipation of mitochondrial membrane potential and the increase in mitochondrial calcium, implying a protective role against oxidative damage in mitochondrial membrane. Similarly, FUM pre-treatment diminished H2O2-induced apoptosis, as evidenced by the reduction in caspase-3 activity and expression; inmunoblot analysis also revealed a decrease in Bax and an increase in Bcl-2 proteins levels. Furthermore, FUM up-regulated the expression of the antioxidant enzymes catalase, superoxide dismutase-1, and hemeoxigenase-1. These findings and the activation of Nrf2 binding activity in nuclear extracts suggest a plausible involvement of Nrf2 signaling pathway in the cytoprotection by FUM. In conclusion, FUM emerges as a potential drug candidate in the therapy of OS-related diseases, such as the neurodegenerative disorders.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University Complutense of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Moriano
authors.affiliation: Department of Plant Biology II, Faculty of Pharmacy, University Complutense of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Divakar
authors.affiliation: Department of Plant Biology II, Faculty of Pharmacy, University Complutense of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Crespo
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University Complutense of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain. Electronic address: pserra@ucm.es.
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Gómez-Serranillos
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism*; D008011:Lichens; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D000068837:Parmeliaceae; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005650:Fumarates; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C026307:fumarprotocetraric acid; D006861:Hydrogen Peroxide
keywords: Apoptosis; Fumarprotocetraric acid; Lichens; Mitochondria; Oxidative stress