Effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice.

TitleEffect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice.
Publication TypeJournal Article
Year of Publication2017
AuteursLitim, N, Morissette, M, Caruso, D, Melcangi, RC, Di Paolo, T
JournalJ Steroid Biochem Mol Biol
Volume174
Pagination242-256
Date Published2017 11
ISSN1879-1220
Keywords5-alpha Reductase Inhibitors, Androgens, Animals, Behavior, Animal, Brain, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dutasteride, Glial Fibrillary Acidic Protein, Male, Mice, Inbred C57BL, MPTP Poisoning, Neuroprotective Agents, Psychomotor Performance, Receptors, Dopamine D1, Receptors, Dopamine D2, Testosterone Congeners, Vesicular Monoamine Transport Proteins
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.

DOI10.1016/j.jsbmb.2017.09.021
Alternate JournalJ. Steroid Biochem. Mol. Biol.
PubMed ID28982631
Grant ListMOP-82692 / / CIHR / Canada