title: Ceruloplasmin is an endogenous protectant against kainate neurotoxicity.
abstract: To determine the role of ceruloplasmin (Cp) in epileptic seizures, we used a kainate (KA) seizure animal model and examined hippocampal samples from epileptic patients. Treatment with KA resulted in a time-dependent decrease in Cp protein expression in the hippocampus of rats. Cp-positive cells were colocalized with neurons or reactive astrocytes in KA-treated rats and epileptic patient samples. KA-induced seizures, initial oxidative stress (i.e., hydroxyl radical formation, lipid peroxidation, protein oxidation, and synaptosomal reactive oxygen species), altered iron status (increasing Fe(2+) accumulation and L-ferritin-positive reactive microglial cells and decreasing H-ferritin-positive neurons), and impaired glutathione homeostasis and neurodegeneration (i.e., Fluoro-Nissl and Fluoro-Jade B staining analyses) were more pronounced in Cp antisense oligonucleotide (ASO)- than in Cp sense oligonucleotide-treated rats. Consistently, Cp ASO facilitated KA-induced lactate dehydrogenase (LDH) release, Fe(2+) accumulation, and glutathione loss in neuron-rich and mixed cultures. However, Cp ASO did not alter KA-induced LDH release or Fe(2+) accumulation in the astroglial culture, but did facilitate impairment in glutathione homeostasis in the same culture. Importantly, treatment with human Cp protein resulted in a significant attenuation against these neurotoxicities induced by Cp ASO. Our results suggest that Cp-mediated neuroprotection occurs via the inhibition of seizure-associated oxidative damage (including impairment in glutathione homeostasis), Fe(2+) accumulation, and alterations in ferritin immunoreactivity. Moreover, interactive modulation between neurons and glia was found to be important for Cp upregulation in the attenuation of epileptic damage in both animals and humans.
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 110-799, South Korea.
authors.forename: Chun Kee
authors.initials: CK
authors.lastname: Chung
authors.affiliation: Department of Anatomy and Cell Biology, Medical School, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Dae-Joong
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Veterinary Medicine, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Myung-Bok
authors.initials: MB
authors.lastname: Wie
authors.affiliation: Department of Pathology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea.
authors.forename: Eon Sub
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Yunsung
authors.initials: Y
authors.lastname: Nam
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: The-Vinh
authors.initials: TV
authors.lastname: Tran
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Sung Youl
authors.initials: SY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Ewha Women׳s University, Seoul 120-750, South Korea.
authors.forename: Hwa-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy, National University of Singapore, Singapore 119260, Singapore.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Ong
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea. Electronic address: kimhc@kangwon.ac.kr.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002570:Ceruloplasmin / Q000502:physiology*; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D007608:Kainic Acid; D015227:Lipid Peroxidation; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D017665:Hydroxyl Radical; D002570:Ceruloplasmin; D005978:Glutathione; D007608:Kainic Acid
keywords: Ceruloplasmin; Epileptic patients; Ferritin; Free radicals; Glia; Glutathione; Hippocampus; Iron; Kainate; Oxidative stress