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      Gender Differences in Methamphetamine-Induced mRNA Associated with Neurodegeneration in the Mouse Nigrostriatal Dopaminergic System

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          In this report female and male CD-1 mice were treated with a neurotoxic regimen of methamphetamine (MA) to compare gender differences in striatal dopamine depletion and concordant changes in mRNA markers of the transforming growth factor-β injury response associated with neurodegeneration. Striatal dopamine concentrations of MA-treated female mice were less depleted and significantly greater than that of identically treated males. Associated with this gender difference in striatal dopamine depletion were significantly decreased mRNA levels of plasminogen activator inhibitor-1 and a trend for increased (p = 0.06) mRNA levels of glial fibrillary acidic protein within females. No statistically significant differences between MA-treated female and male mice were obtained in mRNA levels for transforming growth factor-β, transforming growth factor-β type 2 receptor, activin-like kinase-5 or fibronectin. These data demonstrate the presence of changes in two specific molecular markers of the transforming growth factor-β injury response which are in accordance with gender differences in MA-induced striatal dopamine depletion. The results suggest that the neuroprotective advantage displayed by females may in part be related to reductions in the transforming growth factor-β injury response as indicated by decreased mRNA plasminogen activator inhibitor-1 and an increased response of reactive astrocytes which promote neuronal survival as indicated by augmented glial fibrillary acidic protein mRNA levels.

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          Most cited references 16

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          Transforming growth factor-beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson's disease.

          Transforming growth factor (TGF)-beta 1 content was measured for the first time in the brain (caudate nucleus, putamen, and cerebral cortex) and in ventricular cerebrospinal fluid (VCSF) from control and parkinsonian patients by a sandwich enzyme immunoassay. The concentrations of TGF-beta 1 were significantly higher in the dopaminergic striatal regions in parkinsonian patients than those in controls, but were not significantly different in the cerebral cortex between parkinsonian and control patients. Furthermore, the concentrations of TGF-beta 1 in VCSF were significantly higher in parkinsonian patients than those in non-parkinsonian control patients. Since TGF-beta 1 has potent regulatory activity on cell growth, these results suggest that TGF-beta 1 may have some significant modulatory role in the process of neurodegeneration in Parkinson's disease.
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            Temporal profiling of methamphetamine-induced changes in gene expression in the mouse brain: evidence from cDNA array.

            Methamphetamine (METH) is a neurodegenerative drug of abuse. Its toxicity is characterized by destruction of monoaminergic terminals and by apoptosis in cortical and striatal cell bodies. Multiple factors appear to control METH neurotoxicity, including free radicals and transcription factors. Here, using cDNA arrays, we show the temporal profile of gene expression patterns in the cortex of mice treated with this drug. We obtained two patterns of changes from 588 genes surveyed. First, an early pattern is characterized by upregulation of transcription factors, including members of the jun family. Second, a delayed pattern includes genes related to cell death and to DNA repair. A number of trophic factors were also activated at the later timepoint. These observations suggest that METH can activate a multigene machinery that participates in the production of its toxic effects. The resulting degenerative effects of the drug are thus the result of a balance between protoxic and antiapoptotic mechanisms triggered by its administration to these animals. These observations are of clinical relevance because of the recent identification of degenerative changes in the brains of METH abusers. Copyright 2001 Wiley-Liss, Inc.
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              Influence of strict, intermediate, and broad diagnostic criteria on the age- and sex-specific incidence of Parkinson's disease.

              We studied the influence of three sets of diagnostic criteria on the age- and sex-specific incidence of Parkinson's disease (PD) among residents of Olmsted County, Minnesota, for the period 1976 to 1990. Incidence cases of parkinsonism were detected using the medical records-linkage system of the Rochester Epidemiology Project. PD was separated from other types of parkinsonism using strict, intermediate, and broad criteria. We found 154 incident cases of PD using the strict criteria, 215 using the intermediate criteria, and 266 using the broad criteria. The incidence rate was consistently higher for men across all ages with all three sets of criteria; however, sex differences were more striking at older ages when using the broad criteria. In men above age 79 years, the incidence rate of PD declined with strict criteria, remained stable with intermediate criteria, and increased with broad criteria. The impact of diagnostic criteria on the age-specific incidence curve was less striking for women. When using the broad criteria, the risk of PD increased constantly with age in both sexes, suggesting that PD is an aging-related disease. Our findings suggest that the diagnostic criteria used to separate PD from other types of parkinsonism influence the magnitude of PD incidence and its distribution by age and sex.

                Author and article information

                S. Karger AG
                April 2003
                21 May 2003
                : 77
                : 4
                : 232-238
                aDepartment of Anatomy, Northeastern Ohio Universities College of Medicine (NEOUCOM), Rootstown, Ohio, and bDepartment of Renal Pharmacology, GlaxoSmithKline, King of Prussia, Pa., USA
                70278 Neuroendocrinology 2003;77:232–238
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 1, References: 54, Pages: 7
                Sex Steroids and Reproductive Neuroendocrinology


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