Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease?

Morale, Maria Concetta; L’Episcopo, Francesca; Tirolo, Cataldo; Giovanna, Giaquinta; Caniglia, Salvatore; Testa, Nuccio; Arcieri, P.; Serra, Pier Andrea; Lupo, Gabriella; Alberghina, Mario; Harada, Nobuhiro; Honda, Shin‐ichiro; Panzica, Giancarlo; Marchetti, Bianca

doi:10.1016/j.brainresrev.2007.10.011

Cited by 52 publications

(43 citation statements)

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“…Brain CYPs are also involved in the progression of PD (36). Morale et al (37) reported that loss of aromatase cytochrome P450 function is a risk factor for PD, and McCann et al (38) discovered that the poor metabolizer genotype of CYP2D6 has a significant association with PD.…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of microarray datasets to identify Parkinson's disease-associated pathways and genes

Feng¹,

Wang²

2017

Molecular Medicine Reports

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In order to investigate commonly disturbed genes and pathways in various brain regions of patients with Parkinson's disease (PD), microarray datasets from previous studies were collected and systematically analyzed. Different normalization methods were applied to microarray datasets from different platforms. A strategy combining gene co-expression networks and clinical information was adopted, using weighted gene co-expression network analysis (WGCNA) to screen for commonly disturbed genes in different brain regions of patients with PD. Functional enrichment analysis of commonly disturbed genes was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Co-pathway relationships were identified with Pearson's correlation coefficient tests and a hypergeometric distribution-based test. Common genes in pathway pairs were selected out and regarded as risk genes. A total of 17 microarray datasets from 7 platforms were retained for further analysis. Five gene coexpression modules were identified, containing 9,745, 736, 233, 101 and 93 genes, respectively. One module was significantly correlated with PD samples and thus the 736 genes it contained were considered to be candidate PD-associated genes. Functional enrichment analysis demonstrated that these genes were implicated in oxidative phosphorylation and PD. A total of 44 pathway pairs and 52 risk genes were revealed, and a risk gene pathway relationship network was constructed. Eight modules were identified and were revealed to be associated with PD, cancers and metabolism. A number of disturbed pathways and risk genes were unveiled in PD, and these findings may help advance understanding of PD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Systematic analysis of microarray datasets to identify Parkinson's disease-associated pathways and genes

Feng¹,

Wang²

2017

Molecular Medicine Reports

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“…Aromatase up-regulation (principally in glial cells) and estradiol synthesis at the site of excitotoxic and ischemic brain injury is thought to be an important neuroprotective mechanism Azcoitia et al, 2005;Carswell et al, 2005;GarciaOvejero et al, 2005). Recent studies using either central administration of an aromatase inhibitor (McArthur et al, 2007b) or ArKO mice (Morale et al, 2008) suggest that local production of estradiol is also protective against 6-OHDA-induced toxicity in both the male and female striatum. This contrasts with the sexually dimorphic effects of systemic estradiol, which is universally protective against experimental parkinsonism in female, but not male brains.…”

Section: Brain Aromatase Confers Protection In Male and Female Experimentioning

confidence: 99%

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

2010

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“…Studies using aromatase knockout mice demonstrated that aromatase deficiency leads to susceptibility of neurons to neuronal apoptosis in the frontal cortex of aged females (2) and in the hypothalamus of aged males (3). These mice are also susceptible to neuronal toxins such as domoic acid (4) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is used to produce animal models of Parkinson's disease (5). In behavior studies, aromatase knockout mice exhibit depressive-like behavior (6), aggressive behaviors leading to infanticide (7,8), repressed aggression to intruders (9,10), impaired spatial reference memory (11), and disrupted sexual behavior (7,10).…”

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confidence: 99%

¹¹C-Cetrozole: An Improved C-¹¹C-Methylated PET Probe for Aromatase Imaging in the Brain

Takahashi¹,

Hosoya

Onoe³

et al. 2014

J Nucl Med

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Aromatase (an enzyme that converts androgens to estrogens) in the brain is involved in neuroprotection, synaptic plasticity, and regulation of sexual and emotional behaviors. To investigate the physiologic and pathologic importance of aromatase in the brain, including in humans, we here report the development of a novel PET probe for aromatase, 11 C-cetrozole, which allows noninvasive quantification of aromatase expression. Methods: 11 C-cetrozole was synthesized by the C-11 C-methylation method developed by our group. In vitro autoradiography of frozen sections and a binding study with rat brain homogenates were conducted to demonstrate the specific binding and the dissociation constant. PET studies with anesthetized rhesus monkeys were performed to analyze the dynamics in the brain. Results: In vitro and in vivo studies using 11 C-cetrozole showed its superiority in brain aromatase imaging in terms of specificity and selectivity, compared with previously developed 11 C-vorozole. PET studies showed that 11 C-cetrozole had a higher signal-to-noise ratio, providing a sharper image than 11 C-vorozole, because the radioactive metabolite of 11 C-vorozole was taken up into the brain. High specific binding of 11 C-cetrozole was observed in the amygdala and hypothalamus, and we also noted binding in the nucleus accumbens of rhesus monkeys for the first time. Conclusion: These results suggest that PET imaging with newly developed 11 C-cetrozole is suitable for quantifying the expression of brain aromatase in vivo, possibly providing critical information regarding the functional roles of aromatase in human neurologic and emotional disorders.

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Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease?

Cited by 52 publications

References 113 publications

Systematic analysis of microarray datasets to identify Parkinson's disease-associated pathways and genes

Systematic analysis of microarray datasets to identify Parkinson's disease-associated pathways and genes

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

¹¹C-Cetrozole: An Improved C-¹¹C-Methylated PET Probe for Aromatase Imaging in the Brain

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Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease?

Cited by 52 publications

References 113 publications

Systematic analysis of microarray datasets to identify Parkinson's disease-associated pathways and genes

Systematic analysis of microarray datasets to identify Parkinson's disease-associated pathways and genes

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

11C-Cetrozole: An Improved C-11C-Methylated PET Probe for Aromatase Imaging in the Brain

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¹¹C-Cetrozole: An Improved C-¹¹C-Methylated PET Probe for Aromatase Imaging in the Brain