title: Systemic administration of neuregulin-1β1 protects dopaminergic neurons in a mouse model of Parkinson's disease.
abstract: Neuregulin-1 (Nrg1) is genetically linked to schizophrenia, a disease caused by neurodevelopmental imbalance in dopaminergic function. The Nrg1 receptor ErbB4 is abundantly expressed on midbrain dopaminergic neurons. Nrg1 has been shown to penetrate blood-brain barrier, and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice. These data prompted us to study the effect of peripheral administration of Nrg1 in the context of Parkinson's disease, a neurodegenerative disorder affecting the dopaminergic system in the adult brain. We observed that systemic injections of the extracellular domain of Nrg1β(1) (Nrg1β(1)-ECD) increased dopamine levels in the substantia nigra and striatum of adult mice. Nrg1β(1)-ECD injections also significantly protected the mouse nigrostriatal dopaminergic system morphologically and functionally against 6-hydroxydopamine-induced toxicity in vivo. Moreover, Nrg1β(1)-ECD also protected human dopaminergic neurons in vitro against 6-hydroxydopamine. In conclusion, we have identified Nrg1β(1)-ECD as a neurotrophic factor for adult mouse and human midbrain dopaminergic neurons with peripheral administratability, warranting further investigation as therapeutic option for Parkinson's disease patients.
authors.affiliation: Experimental Neurology, Department of Neurology, Philipps-University, Marburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carlsson
authors.forename: Friederike R
authors.initials: FR
authors.lastname: Schindler
authors.forename: Matthias
authors.initials: M
authors.lastname: Höllerhage
authors.forename: Candan
authors.initials: C
authors.lastname: Depboylu
authors.forename: Oscar
authors.initials: O
authors.lastname: Arias-Carrión
authors.forename: Stefan
authors.initials: S
authors.lastname: Schnurrbusch
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Rösler
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wozny
authors.forename: Gerhard P
authors.initials: GP
authors.lastname: Schwall
authors.forename: Karlfried
authors.initials: K
authors.lastname: Groebe
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Oertel
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.forename: André
authors.initials: A
authors.lastname: Schrattenholz
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020890:Neuregulin-1 / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1; D004298:Dopamine