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: Eun-Joo Shin, Ji Hoon Jeong, Chun Kee Chung, Dae-Joong Kim, Myung-Bok Wie, Eon Sub Park, Yoon Hee Chung, Yunsung Nam, The-Vinh Tran, Sung Youl Lee, Hwa-Jung Kim, Wei-Yi Ong, Hyoung-Chun Kim
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 84 Pg. 355-372 (Jul 2015) ISSN: 1873-4596 [Electronic] United States
• PMID: 25843655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Hydroxyl Radical
• Ceruloplasmin
• Glutathione
• Kainic Acid

Topics

• Adolescent
• Adult
• Animals
• CA1 Region, Hippocampal (metabolism, pathology)
• Case-Control Studies
• Ceruloplasmin (physiology)
• Epilepsy (chemically induced, metabolism)
• Female
• Glutathione (metabolism)
• Humans
• Hydroxyl Radical (metabolism)
• Kainic Acid
• Lipid Peroxidation
• Male
• Middle Aged
• Oxidative Stress
• Rats, Sprague-Dawley
• Young Adult