title: Cytidine 5'-diphosphocholine (CDP-choline) adversely effects on pilocarpine seizure-induced hippocampal neuronal death.
abstract: Citicoline (CDP-choline; cytidine 5'-diphosphocholine) is an important intermediate in the biosynthesis of cell membrane phospholipids. Citicoline serves as a choline donor in the biosynthetic pathways of acetylcholine and neuronal membrane phospholipids, mainly phosphatidylcholine. The ability of citicoline to reverse neuronal injury has been tested in animal models of cerebral ischemia and clinical trials have been performed in stroke patients. However, no studies have examined the effect of citicoline on seizure-induced neuronal death. To clarify the potential therapeutic effects of citicoline on seizure-induced neuronal death, we used an animal model of pilocarpine-induced epilepsy. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25mg/kg) in adult male rats. Citicoline (100 or 300 mg/kg) was injected into the intraperitoneal space two hours after seizure onset and a second injection was performed 24h after the seizure. Citicoline was injected once per day for one week after pilocarpine- or kainate-induced seizure. Neuronal injury and microglial activation were evaluated at 1 week post-seizure. Surprisingly, rather than offering protection, citicoline treatment actually enhanced seizure-induced neuronal death and microglial activation in the hippocampus compared to vehicle treated controls. Citicoline administration after seizure-induction increased immunoglobulin leakage via BBB disruption in the hippocampus compared with the vehicle-only group. To clarify if this adverse effect of citicoline is generalizable across alternative seizure models, we induced seizure by kainate injection (10mg/kg, i.p.) and then injected citicoline as in pilocarpine-induced seizure. We found that citicoline did not modulate kainate seizure-induced neuronal death, BBB disruption or microglial activation. These results suggest that citicoline may not have neuroprotective effects after seizure and that clinical application of citicoline after seizure needs careful consideration.
authors.affiliation: Department of Physiology, Hallym University, College of Medicine, Chuncheon, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Neurology, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
authors.forename: Dong Won
authors.initials: DW
authors.lastname: Lee
authors.affiliation: Department of Physiology, Hallym University, College of Medicine, Chuncheon, Republic of Korea.
authors.forename: Bo Young
authors.initials: BY
authors.lastname: Choi
authors.affiliation: Inha University, Department of Nursing, Incheon, Republic of Korea.
authors.forename: Min
authors.initials: M
authors.lastname: Sohn
authors.affiliation: Department of Neurology, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
authors.forename: Song Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Neurology, College of Medicine, Hallym University, Chuncheon, Republic of Korea; Hallym Institute of Epilepsy Research, Hallym University, Chuncheon 200-702, Republic of Korea.
authors.forename: Hui Chul
authors.initials: HC
authors.lastname: Choi
authors.affiliation: Department of Neurology, College of Medicine, Hallym University, Chuncheon, Republic of Korea; Hallym Institute of Epilepsy Research, Hallym University, Chuncheon 200-702, Republic of Korea. Electronic address: hksong0@paran.com.
authors.forename: Hong Ki
authors.initials: HK
authors.lastname: Song
authors.affiliation: Department of Physiology, Hallym University, College of Medicine, Chuncheon, Republic of Korea; Hallym Institute of Epilepsy Research, Hallym University, Chuncheon 200-702, Republic of Korea. Electronic address: swsuh@hallym.ac.kr.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Suh
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D039481:CD11b Antigen / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003566:Cytidine Diphosphate Choline / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000150:complications / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005452:Fluoresceins; D006624:Hippocampus / Q000473:pathology*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D017628:Microglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018697:Nootropic Agents / Q000009:adverse effects*; D010862:Pilocarpine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D039481:CD11b Antigen; D018690:Excitatory Amino Acid Agonists; D005452:Fluoresceins; D018697:Nootropic Agents; C435731:fluoro jade; D010862:Pilocarpine; D003566:Cytidine Diphosphate Choline; D007608:Kainic Acid
keywords: Blood brain barrier; Citicoline; Kainate; Microglia; Neuron death; Pilocarpine; Seizure; Temporal lobe epilepsy