title: Allopregnanolone reinstates tyrosine hydroxylase immunoreactive neurons and motor performance in an MPTP-lesioned mouse model of Parkinson's disease.
abstract: Restorative/protective therapies to restore dopamine neurons in the substantia nigra pars compacta (SNpc) are greatly needed to effectively change the debilitating course of Parkinson's disease. In this study, we tested the therapeutic potential of a neurogenic neurosteroid, allopregnanolone, in the restoration of the components of the nigrostriatal pathway in MPTP-lesioned mice by measuring striatal dopamine levels, total and tyrosine hydroxylase immunoreactive neuron numbers and BrdU-positive cells in the SNpc. An acute treatment (once/week for two weeks) with allopregnanolone restored the number of tyrosine hydroxylase-positive and total cell numbers in the SNpc of MPTP-lesioned mice, even though this did not increase striatal dopamine. It was also noted that MPTP treated mice to which allopregnanolone was administered had an increase in BrdU-positive cells in the SNpc. The effects of allopregnanolone in MPTP-lesioned mice were more apparent in mice that underwent behavioral tests. Interestingly, mice treated with allopregnanolone after MPTP lesion were able to perform at levels similar to that of non-lesioned control mice in a rotarod test. These data demonstrate that allopregnanolone promotes the restoration of tyrosine hydroxylase immunoreactive neurons and total cells in the nigrostriatal tract, improves the motor performance in MPTP-treated mice, and may serve as a therapeutic strategy for Parkinson's disease.
authors.affiliation: Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Adeosun
authors.forename: Xu
authors.initials: X
authors.lastname: Hou
authors.forename: Yun
authors.initials: Y
authors.lastname: Jiao
authors.forename: Baoying
authors.initials: B
authors.lastname: Zheng
authors.forename: Sherry
authors.initials: S
authors.lastname: Henry
authors.forename: Rosanne
authors.initials: R
authors.lastname: Hill
authors.forename: Zhi
authors.initials: Z
authors.lastname: He
authors.forename: Amar
authors.initials: A
authors.lastname: Pani
authors.forename: Patrick
authors.initials: P
authors.lastname: Kyle
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ou
authors.forename: Thomas
authors.initials: T
authors.lastname: Mosley
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Farley
authors.forename: Craig
authors.initials: C
authors.lastname: Stockmeier
authors.forename: Ian
authors.initials: I
authors.lastname: Paul
authors.forename: Steven
authors.initials: S
authors.lastname: Bigler
authors.forename: Roberta Diaz
authors.initials: RD
authors.lastname: Brinton
authors.forename: Richard
authors.initials: R
authors.lastname: Smeyne
authors.forename: Jun Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011280:Pregnanolone / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D011280:Pregnanolone; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine