title: The 5α-reductase inhibitor Dutasteride but not Finasteride protects dopamine neurons in the MPTP mouse model of Parkinson's disease.
abstract: Finasteride and Dutasteride are 5α-reductase inhibitors used in the clinic to treat endocrine conditions and were recently found to modulate brain dopamine (DA) neurotransmission and motor behavior. We investigated if Finasteride and Dutasteride have a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) male mice as a model of Parkinson's disease (PD). Experimental groups included saline treated controls and mice treated with saline, Finasteride (5 and 12.5 mg/kg) or Dutasteride (5 and 12.5 mg/kg) for 5 days before and 5 days after MPTP administration (4 MPTP injections, 6.5 mg/kg on day 5 inducing a moderate DA depletion) and then they were euthanized. MPTP administration decreased striatal DA contents measured by HPLC while serotonin contents remained unchanged. MPTP mice treated with Dutasteride 5 and 12.5 mg/kg had higher striatal DA and metabolites (DOPAC and HVA) contents with a decrease of metabolites/DA ratios compared to saline-treated MPTP mice. Finasteride had no protective effect on striatal DA contents. Tyrosine hydroxylase (TH) mRNA levels measured by in situ hybridization in the substantia nigra pars compacta were unchanged. Dutasteride at 12.5 mg/kg reduced the effect of MPTP on specific binding to striatal DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) measured by autoradiography. MPTP reduced compared to controls plasma testosterone (T) and dihydrotestosterone (DHT) concentrations measured by liquid chromatography-tandem mass spectrometry; Dutasteride and Finasteride increased plasma T levels while DHT levels remained low. In summary, our results showed that a 5α-reductase inhibitor, Dutasteride has neuroprotective activity preventing in male mice the MPTP-induced loss of several dopaminergic markers.
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada; Faculty of Pharmacy, Laval University, Quebec City, Canada.
authors.forename: Nadhir
authors.initials: N
authors.lastname: Litim
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada; Faculty of Pharmacy, Laval University, Quebec City, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bourque
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada; Faculty of Pharmacy, Laval University, Quebec City, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Al Sweidi
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada; Faculty of Pharmacy, Laval University, Quebec City, Canada. Electronic address: therese.dipaolo@crchul.ulaval.ca.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013196:Dihydrotestosterone / Q000097:blood; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000068538:Dutasteride / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D065842:Pars Compacta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D013196:Dihydrotestosterone; D015102:3,4-Dihydroxyphenylacetic Acid; D013739:Testosterone; D018120:Finasteride; D014446:Tyrosine 3-Monooxygenase; D000068538:Dutasteride; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Dopamine; Dutasteride; Finasteride; MPTP; Neuroprotection; Striatum