title: CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice.
abstract: Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered protein, which belongs to the evolutionarily conserved CDNF/MANF family of neurotrophic factors. The degeneration of dopamine neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment is well  characterized, and efficacy in this model is considered a standard criterion for development of parkinsonian therapies. MPTP is a neurotoxin, which produces parkinsonian symptoms in humans and in C57/Bl6 mice. To date, there are no reports about the effects of CDNF on dopamine neuron survival  or function in the MPTP rodent model, a critical gap. Therefore, we studied whether CDNF has neuroprotective and neurorestorative properties for the nigrostriatal dopamine system after MPTP injections in C57/Bl6 mice. We found that bilateral striatal CDNF injections, given 20 h before MPTP,  improved horizontal and vertical motor behavior. CDNF pretreatment increased tyrosine hydroxylase (TH) immunoreactivity in the striatum and in the substantia nigra pars reticulata (SNpr), as well as the number of TH-positive cells in substantia nigra pars compacta (SNpc). Posttreatment with  CDNF, given 1 week after MPTP injections, increased horizontal and vertical motor behavior of mice, as well as dopamine fiber densities in the striatum and the number of TH-positive cells in SNpc. CDNF did not alter any of the analyzed dopaminergic biomarkers or locomotor behavior in MPTP-untreated  animals. We conclude that striatal CDNF administration is both neuroprotective and neurorestorative for the TH-positive cells in the nigrostriatal dopamine system in the MPTP model, which supports the development of CDNF-based treatment for Parkinson's disease.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA.
authors.forename: Mikko
authors.initials: M
authors.lastname: Airavaara
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.forename: Merja H
authors.initials: MH
authors.lastname: Voutilainen
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Jenny
authors.initials: J
authors.lastname: Chou
authors.forename: Päivi
authors.initials: P
authors.lastname: Lindholm
authors.forename: Maria
authors.initials: M
authors.lastname: Lindahl
authors.forename: Raimo K
authors.initials: RK
authors.lastname: Tuominen
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
authors.forename: Barry
authors.initials: B
authors.lastname: Hoffer
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D020267:MPTP Poisoning / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; C522218:cdnf protein, mouse; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine