title: Castration induces Parkinson disease pathologies in young male mice via inducible nitric-oxide synthase.
abstract: Although Parkinson disease (PD) is a progressive neurodegenerative disorder, available animal models do not exhibit irreversible neurodegeneration, and this is a major obstacle in finding out an effective drug against this disease. Here we delineate a new irreversible model to study PD pathogenesis. The model is based on simple castration of young male mice. Levels of inducible nitric-oxide synthase (iNOS), glial markers (glial fibrillary acidic protein and CD11b), and α-synuclein were higher in nigra of castrated male mice than normal male mice. On the other hand, after castration, the level of glial-derived neurotrophic factor (GDNF) markedly decreased in the nigra of male mice. Accordingly, castration also induced the loss of tyrosine hydroxylase-positive neurons in the nigra and decrease in tyrosine hydroxylase-positive fibers and neurotransmitters in the striatum. Reversal of nigrostriatal pathologies in castrated male mice by subcutaneous implantation of 5α-dihydrotestosterone pellets validates an important role of male sex hormone in castration-induced nigrostriatal pathology. Interestingly, castration was unable to cause glial activation, decrease nigral GDNF, augment the death of nigral dopaminergic neurons, induce the loss of striatal fibers, and impair neurotransmitters in iNOS(-/-) male mice. Furthermore, we demonstrate that iNOS-derived NO is responsible for decreased expression of GDNF in activated astrocytes. Together, our results suggest that castration induces nigrostriatal pathologies via iNOS-mediated decrease in GDNF. These results are important because castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study PD-related nigrostriatal pathologies, paving the way for easy drug screening against PD.
authors.affiliation: From the Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Khasnavis
authors.affiliation: From the Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Anamitra
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: From the Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Avik
authors.initials: A
authors.lastname: Roy
authors.affiliation: From the Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612. Electronic address: kalipada_pahan@rush.edu.
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002369:Castration / Q000009:adverse effects*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D020249:Hormone Replacement Therapy; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology* / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000008:administration & dosage / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D018836:Inflammation Mediators; D051844:alpha-Synuclein; D009569:Nitric Oxide; D013739:Testosterone; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Castration; Microglia; Neurodegeneration; Neuroinflammation; Nitric-oxide Synthase; Parkinson Disease