title: Continuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson's disease model of rats with enhanced neurogenesis.
abstract: Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neuronal systems. Several therapeutic tools for PD include medication using L-DOPA and surgeries such as deep brain stimulation are established. However, the therapies are considered as symptomatic therapy, but not basic remedy for PD and a new regenerative therapy would be desired to explore. In this study, the neuroprotective/rescue effects of erythropoietin (EPO), a well known hematopoietic hormone, on dopaminergic neurons were explored with neurogeneic potencies of EPO. EPO (100 IU/day) was continuously administered with micro-osmotic pump for a week to PD model of rats induced by intrastriatal 6-hydroxydopamine (6-OHDA) injection with subsequent behavioral and immunohistochemical investigations. The number of amphetamine-induced rotations of EPO-treated rats significantly decreased, compared to the control rats. The preservation of dopaminergic neurons of EPO-treated rats were confirmed by tyrosine hydroxylase staining and Fluoro-Gold staining. The number of bromodeoxyuridine (BrdU)/polysialic acid-neural cell adhesion molecule (PSA-NCAM) double positive cells in the subventricular zone of EPO treated rats significantly increased with migratory potencies to the damaged striatum,compared to the control rats. Furthermore, TUNEL staining and phosphorylated Akt staining revealed that the neuroprotective/rescue effects of EPO might be mediated by anti-apoptotic effects through the increase of phosphorylated Akt. These results suggest that continuous low dose infusion of EPO exerts neuroprotective/rescue effects with neurogeneic potentials. EPO might be a strong tool for PD therapy, although the further experiments should be added.
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 2-5-1, Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Kadota
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shingo
authors.forename: Takao
authors.initials: T
authors.lastname: Yasuhara
authors.forename: Naoki
authors.initials: N
authors.lastname: Tajiri
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kondo
authors.forename: Takamasa
authors.initials: T
authors.lastname: Morimoto
authors.forename: Wen Ji
authors.initials: WJ
authors.lastname: Yuan
authors.forename: Feifei
authors.initials: F
authors.lastname: Wang
authors.forename: Tanefumi
authors.initials: T
authors.lastname: Baba
authors.forename: Koji
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyoshi
authors.forename: Isao
authors.initials: I
authors.lastname: Date
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016627:Oxidopamine / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000378:metabolism; D013266:Stilbamidines; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D019006:Neural Cell Adhesion Molecules; D018696:Neuroprotective Agents; D012794:Sialic Acids; D013266:Stilbamidines; C021319:polysialic acid; D004921:Erythropoietin; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D051057:Proto-Oncogene Proteins c-akt; D001973:Bromodeoxyuridine; D004298:Dopamine