Effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice. Issue 174 (November 2017)

• Record Type: Journal Article
• Authors: Litim, Nadhir; Morissette, Marc; Caruso, Donatella; Melcangi, Roberto C.; Di Paolo, Thérèse
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 174(2017)
• Page Start: 242
• Page End: 256
• Publication Date: 2017-11
• Subjects: 3α-diol 5α-androstane-3α, 17β-diol -- 3β-diol 5α-androstane-3β, 17β-diol -- 5-HIAA 5-hydroxyindoleacetic acid -- 5-HT serotonin -- DA dopamine -- DAT dopamine transporter -- DHEA dehydroepiandrosterone -- DHP 5α-dihydroprogesterone -- DHT dihydrotestosterone -- DOPAC 3, 4-dihydroxyphenylacetic acid -- ERK extracellular signal–regulated kinase -- GFAP glial fibrillary acidic protein -- GSK3β glycogen synthase kinase 3β -- HPLC high performance liquid chromatography -- HVA homovanillic acid -- Iba1 ionized calcium binding adapter molecule 1 -- ISOPREG isopregnanolone -- L-DOPA Levodopa -- LID Levodopa-induced dyskinesias -- MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine -- PD Parkinson's disease -- PREG pregnenolone -- PROG progesterone -- PVDF polyvinylidine difluoride -- RIPA radioimmunoprecipitation assay -- SNpc substantia nigra pars compacta -- TH tyrosine hydroxylase -- THP tetrahydroprogesterone or allopregnanolone -- VMAT2 vesicular monoamine transporter 2; Parkinson's disease -- MPTP -- Neuroprotection -- Basal ganglia -- Astrocyte; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.09.021
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Dutasteride prevented the MPTP-induced striatal loss of dopamine contents. Dutasteride prevented striatal MPTP-induced loss of DAT and VMAT2 transporters. Dutasteride increased striatal DAT binding and glycosylation. Dutasteride affected androgen and progesterone metabolism in brain and plasma. Dutasteride prevented MPTP-induced increase of GFAP. Abstract: Dutasteride is a 5alpha-reductase inhibitor in clinical use to treat endocrine conditions. The present study investigated the neuroprotective mechanisms of action of dutasteride in intact and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-lesioned mice using a low dose of MPTP not affecting motor activity modeling early stages of Parkinson's disease (PD). We hypothesized that dutasteride neuroprotection is due to altered steroids levels. Dutasteride pre-treatment prevented loss of striatal dopamine (DA) and its metabolite DOPAC. Dutasteride decreased effects of MPTP on striatal dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2) and D2 DA receptor specific binding while D1 receptor specific binding remained unchanged. Dutasteride enhanced DAT specific binding and the glycosylated form of DAT in intact mice. MPTP-lesioned mice had plasma and brain testosterone and dihydrotestosterone levels lower than control mice whereas progesterone and its metabolites (dihydroprogesterone, isopregnanolone and tetrahydroprogesterone) pathway showed increases. Dutasteride treatment by inhibiting transformation of progesterone and testosterone to its metabolites elevated plasma and brain concentrations of testosterone compared to MPTP mice and decreased DHT levels in intact mice. Plasma and brain estradiol levels were low and remained unchanged by MPTP and/or dutasteride treatment. Dutasteride treatment did not affect striatal phosphorylation of Akt and its downstream substrate GSK3β as well as phosphorylation of ERK1/2 in intact and MPTP lesioned MPTP mice. Striatal glial fibrillary acidic protein (GFAP) levels were markedly elevated in MPTP compared to control mice and dutasteride reduced GFAP levels in MPTP mice. Treatment with dutasteride post-lesion left unchanged striatal DA levels. These results suggest dutasteride as promising drug for PD neuroprotection.