title: Ephrin-A1-mediated dopaminergic neurogenesis and angiogenesis in a rat model of Parkinson's disease.
abstract: Cells of the neural stem cell lineage in the adult subventricular zone (SVZ) respond to brain insult by increasing their numbers and migrating through the rostral migratory stream. However, in most areas of the brain other than the SVZ and the subgranular zone of the dentate gyrus, such a regenerative response is extremely weak. Even these two neurogenic regions do not show extensive regenerative responses to repair tissue damage, suggesting the presence of an intrinsic inhibitory microenvironment (niche) for stem cells. In the present study, we assessed the effects of injection of clustered ephrin-A1-Fc into the lateral ventricle of rats with unilateral nigrostriatal dopamine depletion. Ephrin-A1-Fc clustered by anti-IgG(Fc) antibody was injected stereotaxically into the ipsilateral lateral ventricle of rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine, and histologic analysis and behavioral tests were performed. Clustered ephrin-A1-Fc transformed the subventricular niche, increasing bromodeoxyuridine-positive cells in the subventricular area, and the cells then migrated to the striatum and differentiated to dopaminergic neurons and astrocytes. In addition, clustered ephrin-A1-Fc enhanced angiogenesis in the striatum on the injected side. Along with histologic improvements, behavioral derangement improved dramatically. These findings indicate that the subventricular niche possesses a mechanism for regulating both stem cell and angiogenic responses via an EphA-mediated signal. We conclude that activation of EphA receptor-mediated signaling by clustered ephrin-A1-Fc from within the lateral ventricle could potentially be utilized in the treatment of neurodegenerative diseases such as Parkinson's disease.
authors.affiliation: Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Jing
authors.forename: Hideto
authors.initials: H
authors.lastname: Miwa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sawada
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakanishi
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Masayasu
authors.initials: M
authors.lastname: Miyajima
authors.forename: Kazushige
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D058948:Cell Tracking; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D036382:Ephrin-A1 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D036385:Ephrin-A4 / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007276:Injections, Intraventricular; D020547:Lateral Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017072:Neostriatum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D036081:Receptors, Eph Family / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D036382:Ephrin-A1; D036385:Ephrin-A4; D007141:Immunoglobulin Fc Fragments; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; C489246:ephrin A1-Fc fusion protein, recombinant; D036081:Receptors, Eph Family; D001973:Bromodeoxyuridine; D004298:Dopamine