title: Domoic acid-induced seizures in California sea lions (Zalophus californianus) are associated with neuroinflammatory brain injury.
abstract: California sea lions (CSLs) exposed to the marine biotoxin domoic acid (DA) develop an acute or chronic toxicosis marked by seizures and act as sentinels of the disease. Experimental evidence suggests that oxidative stress and neuroinflammation are important mechanisms underlying the seizurogenic potential of environmental toxicants but these pathways are relatively unstudied in CSLs. In the current study, we investigated the role of glutamate-glutamine changes and gliosis in DA-exposed CSLs to better understand the neurotoxic mechanisms occurring during DA toxicity. Sections from archived hippocampi from control and CSLs diagnosed with DA toxicosis were immunofluorescently stained for markers of gliosis, oxidative/nitrative stress and changes in glutamine synthetase (GS). Quantitative assessment revealed increasing loss of microtubule associated protein-2 positive neurons with elevations in 4-hydroxynonenal correlating with chronicity of exposure, whereas the pattern of activated glia expressing nitric oxide synthase 2 and tumor necrosis factor followed pathological severity. There was no significant change in the amount of GS positive cells but there was increased 3-nitrotyrosine in GS expressing cells and in neurons, particularly in animals with chronic DA toxicosis. These changes were consistently seen in the dentate gyrus and in the cornu ammonis (CA) sectors CA3, CA4, and CA1. The results of this study indicate that gliosis and resultant changes in GS are likely important mechanisms in DA-induced seizure that need to be further explored as potential therapies in treating exposed wildlife.
authors.affiliation: Center for Environmental Medicine, Colorado State University, Fort Collins, CO, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Kirkley
authors.affiliation: Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Madl
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Duncan
authors.affiliation: The Marine Mammal Center, 1065 Fort Cronkhite, Sausalito, CA 94965, USA.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Gulland
authors.affiliation: Center for Environmental Medicine, Colorado State University, Fort Collins, CO, USA. Electronic address: Ron.tjalkens@colostate.edu.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Tjalkens
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D046070:Sea Lions / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D014874:Water Pollutants, Chemical; D005974:Glutamate-Ammonia Ligase; C012301:domoic acid; D007608:Kainic Acid
keywords: California sea lion; Domoic acid; Gliosis; Glutamine synthetase; Neuroinflammation; Oxidative stress