title: Striatal susceptibility to a dopaminergic neurotoxin is independent of sex hormone effects on cell survival and DAT expression but is exacerbated by central aromatase inhibition.
abstract: The aim of this study was to investigate further the hormone-dependent processes underlying sex differences in neurotoxic responses within the rat nigrostriatal dopaminergic (NSDA) pathway after partial lesioning with 6-OHDA, a state thought to mimic the early stages of Parkinson's disease where, in humans and animal models alike, males appear to be more susceptible. Contrary to our hypotheses, hormone manipulations (gonadectomy +/- oestrogen or androgen treatment) failed to alter survival of tyrosine hydroxylase immunoreactive cells in the substantia nigra pars compacta (SNc) after lesioning; this indicates that, unlike inherent sex differences in toxin-induced striatal dopamine depletion, sex differences in cell loss were not hormonally generated, and that hormone-dependent changes in dopamine depletion can occur independently of cell survival. In addition, hormonally induced changes in striatal expression of the dopamine transporter (DAT), an important factor for 6-OHDA toxicity, did not correlate with hormonal influences on striatal dopamine loss and, in males, central inhibition of aromatase prior to 6-OHDA infusion exacerbated striatal dopamine loss with no effect on SNc tyrosine hydroxylase-immunoreactive survival, suggesting locally generated oestrogen is neuroprotective. These results support the novel view that sex steroid hormones produced peripherally and centrally play a significant, sex-specific role within the sexually dimorphic NSDA pathway to modulate plastic, compensatory responses aimed at restoring striatal dopamine functionality, without affecting cell loss.
authors.affiliation: Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: McArthur
authors.forename: Hilary E
authors.initials: HE
authors.lastname: Murray
authors.forename: Alihusein
authors.initials: A
authors.lastname: Dhankot
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
authors.forename: Glenda E
authors.initials: GE
authors.lastname: Gillies
mesh_terms: D000077384:Anastrozole; D000818:Animals; D001141:Aromatase / Q000187:drug effects / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D004351:Drug Resistance / Q000187:drug effects / Q000502:physiology; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D016627:Oxidopamine / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D047072:Aromatase Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D004967:Estrogens; D009498:Neurotoxins; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole; D016627:Oxidopamine; D001141:Aromatase; D004298:Dopamine