title: Protective effect of a novel peptide against methylmercury-induced toxicity in rat primary astrocytes.
abstract: Methylmercury (MeHg) is an environmental neurotoxicant associated with aberrant central nervous system (CNS) functions. In this study, we examined the protective effect of a novel anti-inflammatory and cytoprotective nonapeptide, termed IIIM1, against MeHg-induced toxicity in cultured rat neonatal primary astrocytes. Astrocytes were pretreated for 66 h with 5 μg/ml IIIM1 (4.95 μM) followed by 6 h exposure to MeHg (5 μM). MeHg significantly increased F(2)-isoprostane generation, a lipid peroxidation biomarker of oxidative injury and this effect was significantly reduced upon pre-treatment with IIIM1. The MeHg-induced increase in levels of prostaglandin E(2) (PGE(2)), biomarkers of inflammatory responses, was also decreased in the peptide-treated cells. Mass spectrometry analysis revealed no chemical or binding interaction between MeHg and IIIM1, indicating that intracellular cytoprotective mechanism of action accounts for the neuroprotection rather than direct intracellular neutralization of the neurotoxicant with the peptide. These findings point to therapeutic potential for IIIM1 in a plethora of conditions associated with reactive oxygen species (ROS) generation. The implication of these findings may prove beneficial in designing new treatment modalities that efficiently suppress neurotoxicity, triggered not only by MeHg, but also by other metals and environmental agents, as well as chronic disease conditions that inherently increase reactive radical production and inflammatory signaling.
authors.affiliation: Institute of Drug Research, School of Pharmacy, the Hebrew University, 91120 Jerusalem, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Wormser
authors.forename: Berta
authors.initials: B
authors.lastname: Brodsky
authors.forename: Dejan
authors.initials: D
authors.lastname: Milatovic
authors.forename: Yoram
authors.initials: Y
authors.lastname: Finkelstein
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.forename: Joao B
authors.initials: JB
authors.lastname: Rocha
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D028441:F2-Isoprostanes / Q000378:metabolism; D006657:Histones / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D013058:Mass Spectrometry; D008767:Methylmercury Compounds / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D028441:F2-Isoprostanes; D006657:Histones; D018836:Inflammation Mediators; D008767:Methylmercury Compounds; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C530140:lysyl-glycyl-histidyl-tyrosyl-alanyl-glutamyl-arginyl-valyl-glyine