Non-steroidal anti-inflammatory drug use and the risk of Parkinson's disease

BACKGROUND: Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease (PD). METHODS: We investigated associations between use of aspirin, nonaspirin NSAIDs, and acetaminophen and PD in a large population-based case-control study using Danish health and pharmacy registries. We identified 1,931 PD cases reported in hospital or outpatient clinic records who had received a primary diagnosis of PD between 2001 and 2006, and 9,651 age- and sex-matched controls from the Danish population register. Prescription medication use was documented in a pharmacy database covering all residents of Denmark since 1995. RESULTS: Adjusting for age, sex, use of cardiovascular disease drugs, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity scores, and excluding prescriptions filled within 5 years before diagnosis, we found no evidence for an association between PD and either aspirin use (OR = 0.97; 95% CI 0.82, 1.14) or nonaspirin NSAID use (OR = 0.97; 95% CI 0.86, 1.09), regardless of intensity of use; further, there was no association between use of ibuprofen or acetaminophen and PD. CONCLUSION: Our findings provide no evidence for a protective effect of nonaspirin and aspirin NSAID prescription drug use shortly before PD onset

Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia

Copyright @ 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.Muscular Dystrophy Association (USA), the National Health and Medical Research Council (Australia), the Friedreich’s Ataxia Research Alliance (USA), the Brockhoff Foundation (Australia), the Friedreich Ataxia Research Association (Australasia), Seek A Miracle (USA) and the Victorian Government’s Operational Infrastructure Support Program

Distinct genes related to drug response identified in ER positive and ER negative breast cancer cell lines

Breast cancer patients have different responses to chemotherapeutic treatments. Genes associated with drug response can provide insight to understand the mechanisms of drug resistance, identify promising therapeutic opportunities, and facilitate personalized treatment. Estrogen receptor (ER) positive and ER negative breast cancer have distinct clinical behavior and molecular properties. However, to date, few studies have rigorously assessed drug response genes in them. In this study, our goal was to systematically identify genes associated with multidrug response in ER positive and ER negative breast cancer cell lines. We tested 27 human breast cell lines for response to seven chemotherapeutic agents (cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, gemcitabine, and paclitaxel). We integrated publicly available gene expression profiles of these cell lines with their in vitro drug response patterns, then applied meta-analysis to identify genes related to multidrug response in ER positive and ER negative cells separately. One hundred eighty-eight genes were identified as related to multidrug response in ER positive and 32 genes in ER negative breast cell lines. Of these, only three genes (DBI, TOP2A, and PMVK) were common to both cell types. TOP2A was positively associated with drug response, and DBI was negatively associated with drug response. Interestingly, PMVK was positively associated with drug response in ER positive cells and negatively in ER negative cells. Functional analysis showed that while cell cycle affects drug response in both ER positive and negative cells, most biological processes that are involved in drug response are distinct. A number of signaling pathways that are uniquely enriched in ER positive cells have complex cross talk with ER signaling, while in ER negative cells, enriched pathways are related to metabolic functions. Taken together, our analysis indicates that distinct mechanisms are involved in multidrug response in ER positive and ER negative breast cells. © 2012 Shen et al

A role for trypanosomatid aldo-keto reductases in methylglyoxal, prostaglandin and isoprostane metabolism

Trypanosomatid parasites are the infectious agents causing Chagas’ disease, visceral and cutaneous leishmaniasis and human African trypanosomiasis. Recent work of others has implicated an aldo-keto reductase (AKR) in susceptibility and resistance of Trypanosoma cruzi to benznidazole, a drug used to treat Chagas’ disease. Here we show that TcAKR and homologues in the related parasites T. brucei and Leishmania donovani do not reductively activate monocyclic (benznidazole, nifurtimox, fexinidazole) or bicyclic nitro-drugs such as PA824. Rather, these enzymes metabolise a variety of toxic ketoaldehydes, such as glyoxal and methylglyoxal, suggesting a role in cellular defence against chemical stress. UPLC-QToF/MS analysis of benznidazole bio-activation by T. cruzi cell lysates confirms previous reports identifying numerous drug metabolites, including a dihydro-dihydroxy intermediate that can dissociate to form N-benzyl-2-guanidinoacetamide and glyoxal, a toxic DNA glycating and cross-linking agent. Thus, we propose that TcAKR contributes to benznidazole resistance by removal of toxic glyoxal. In addition, three of the four enzymes studied here display activity as prostaglandin F2α synthases, despite the fact that there are no credible cyclooxygenases in these parasites to account for formation of the precursor PGH2 from arachidonic acid. Our studies suggest that arachidonic acid is first converted non-enzymatically in parasite lysates to (PGH2-like) regioisomers by free-radical-mediated peroxidation and that AKRs convert these lipid peroxides into isoprostanes, including prostaglandin F2α and 8-iso-prostaglandin F2α

Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer

We have recently reported a novel function for carbonyl reductase (CR), namely, its ability to modulate the metastatic potential of malignant mouse cells. Because there are currently no data addressing a similar function for CR in human cancers, the aim of this study was to assess a correlation between survival and metastasis, and CR level in epithelial ovarian cancer. Using anti-CR antibody, immunohistochemical staining was performed on 73 epithelial ovarian cancers, 13 borderline malignant tumours, and 25 benign ovarian tumours for a total of 111 specimens. The combined rate for strongly and weakly positive reactions for CR was 32.0% for benign tumours, 38.5% for borderline malignant tumours, and 61.6% for ovarian cancers. The CR-positive rate was 35.7% (weakly positive alone) for ovarian cancers with retroperitoneal lymph node (RLN) metastasis and 67.8% for those without RLN metastasis (P< 0.05). The 5-year survival rate was 62.7% for the patients with CR-negative cancer and 86.1% for those with CR-positive cancer (P< 0.05). The present results indicate that decreased CR expression in epithelial ovarian cancer is associated with RLN metastasis and poor survival.© 2001 Cancer Research Campaignhttp://www.bjcancer.co

Residential exposure to transportation noise in Denmark and incidence of dementia:National cohort study

OBJECTIVE: To investigate the association between long term residential exposure to road traffic and railway noise and risk of incident dementia. DESIGN: Nationwide prospective register based cohort study. SETTING: Denmark. PARTICIPANTS: 1 938 994 adults aged ≥60 years living in Denmark between 1 January 2004 and 31 December 2017. MAIN OUTCOME MEASURES: Incident cases of all cause dementia and dementia subtypes (Alzheimer’s disease, vascular dementia, and Parkinson’s disease related dementia), identified from national hospital and prescription registries. RESULTS: The study population included 103 500 participants with incident dementia, and of those, 31 219 received a diagnosis of Alzheimer’s disease, 8664 of vascular dementia, and 2192 of Parkinson’s disease related dementia. Using Cox regression models, 10 year mean exposure to road traffic and railway noise at the most (L(den)max) and least (L(den)min) exposed façades of buildings were associated with a higher risk of all cause dementia. These associations showed a general pattern of higher hazard ratios with higher noise exposure, but with a levelling off or even small declines in risk at higher noise levels. In subtype analyses, both road traffic noise and railway noise were associated with a higher risk of Alzheimer’s disease, with hazard ratios of 1.16 (95% confidence interval 1.11 to 1.22) for road L(den)max ≥65 dB compared with <45 dB, 1.27 (1.22 to 1.34) for road L(den)min ≥55 dB compared with <40 dB, 1.16 (1.10 to 1.23) for railway L(den)max ≥60 dB compared with <40 dB, and 1.24 (1.17 to 1.30) for railway L(den)min ≥50 dB compared with <40 dB. Road traffic, but not railway, noise was associated with an increased risk of vascular dementia. Results indicated associations between road traffic L(den)min and Parkinson’s disease related dementia. CONCLUSIONS: This nationwide cohort study found transportation noise to be associated with a higher risk of all cause dementia and dementia subtypes, especially Alzheimer’s disease

40 Hz steady-state response in human auditory cortex is shaped by GABAergic neuronal inhibition

The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, noninvasive physiological biomarker for schizophrenia and related neuropsychiatric disorders. The 40 Hz ASSR might be amplified by synaptic interactions in cortical circuits, which are, in turn, disturbed in neuropsychiatric disorders. Here, we tested whether the 40 Hz ASSR in the human auditory cortex depends on two key synaptic components of neuronal interactions within cortical circuits: excitation via N-methyl-aspartate glutamate (NMDA) receptors and inhibition via gamma-amino-butyric acid (GABA) receptors. We combined magnetoencephalography (MEG) recordings with placebo-controlled, low-dose pharmacological interventions in the same healthy human participants (13 males, 7 females). All participants exhibited a robust 40 Hz ASSR in auditory cortices, especially in the right hemisphere, under a placebo. The GABAA receptor–agonist lorazepam increased the amplitude of the 40 Hz ASSR, while no effect was detectable under the NMDA blocker memantine. Our findings indicate that the 40 Hz ASSR in the auditory cortex involves synaptic (and likely intracortical) inhibition via the GABAA receptor, thus highlighting its utility as a mechanistic signature of cortical circuit dysfunctions involving GABAergic inhibition