Effect of ibuprofen on hippocampal gene expression in APP-PS1 mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67306 | GEO | 2016/06/14
SECONDARY ACCESSION(S): PRJNA279470
REPOSITORIES: GEO
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Project description:NSAIDs (non-steroidal anti-inflammatory drugs) inhibit cyclooxygenase (COX) enzymes and prevent Alzheimer's disease (AD) at preclinical stages in cognitively normal aging populations. We modeled NSAID prevention of memory impairment in AD model mice to identify novel targets of NSAID action. We found that the widely-used NSAID ibuprofen prevented early hippocampus-dependent memory deficits in APP-PS1 mice. We therefore analyzed gene expression in the hippocampus of these mice. We treated male APPSwe-PS1deltaE9 mice (strain originally provided by Dr. David Borchelt and fully back-crossed to a C57BL/6J background) and their wild-type littermates with ibuprofen in chow from 3 to 6 months of age, after which we sacrificed the mice and dissected one hippocampus from each mouse for RNA isolation and microarray analysis. In each genotype-treatment group, we analyzed samples from 5 mice. Note: In our initial analysis, we found that sample GSM1644138, Hippocampus_WT_Con_rep5, was an outlier in overall gene expression. We therefore removed this sample before performing the analysis published in PMID 27190010.
2016-06-14 | E-GEOD-67306 | biostudies-arrayexpress
Project description:This study was undertaken to assess the similarities (or differences) between the well-established PPARγ agonist Rosiglitazone and Non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac, indomethacin and ibuprofen, as well as the partial agonist GQ16 at the transcriptome level. Assessment of NSAID and GQ16 activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs and GQ16 display similar effects toward PPARγ-dependent target genes in a manner similar to that of Rosiglitazone.
2015-06-01 | GSE64075 | GEO
Project description:An anthropogenic chemical contaminant commonly identified in aquatic receiving environments is the non-steroidal anti-inflammatory drug (NSAID), ibuprofen(IBF). While the role of ibuprofen in target organisms is known, there exists a paucity of data on the impact of exposure to non-target wildlife species. In the case of frog species, normal development and environmental fitness involves the actions of the thyroid hormones (THs), particularly at key points in the life cycle. We investigated whether exposure of premetamorphic North American bullfrog (Rana catesbeiana) tadpoles to IBF altered their response to treatment with an exogenous dose of thyroid hormone (T3).
2014-09-23 | GSE53565 | GEO
Project description:An anthropogenic chemical contaminant commonly identified in aquatic receiving environments is the non-steroidal anti-inflammatory drug (NSAID), ibuprofen(IBF). While the role of ibuprofen in target organisms is known, there exists a paucity of data on the impact of exposure to non-target wildlife species. In the case of frog species, normal development and environmental fitness involves the actions of the thyroid hormones (THs), particularly at key points in the life cycle. We investigated whether exposure of premetamorphic North American bullfrog (Rana catesbeiana) tadpoles to IBF altered their response to treatment with an exogenous dose of thyroid hormone (T3). Six animals randomly selected from each treatment were examined for the status of the hepatic transcriptome using MAGEX DNA array analysis.
2014-09-23 | E-GEOD-53565 | biostudies-arrayexpress
Project description:NSAIDs and ACE that affect prostaglandin synthesis are widely used by pregnant women. Epidemiological studies have hypothesized a potential relation of testis dysgenesis syndromes such as cryptorchidism and hypospadias to exposure to these molecules during both the first and the second trimesters of gestation. To decipher whether the embryonic gonads themselves are targets for these molecules, we analysed the impact of precocious in utero exposure to NSAIDs and ACE alone or in combination on the early development of the testis during sex determination, using therapeutic doses similar to those administrated in human medications. We found that in utero exposure to ACE, aspirin or ibuprofen affects the germ cell proliferation in embryonic testis. The whole transcriptome of 13.5 dpc (days post coïtum) treated testis suggests different mechanisms of action of these drugs and a functional interaction between both molecules used in combination, in accelerating the germ cell differentiation. We identified that ACE and ibuprofen exposure through the up-regulation of Dnmt3L expression induces advanced epigenetic reprograming of the germline and enhanced glycogen storage within the testis cords through the activation of extracellular matrix genes expression. In addition, we identified for the first time the prostaglandin production pattern in the embryonic gonad and showed that PGD2, PGE2 and PGI2 were the targets of ACE and NSAIDs drugs. These features might affect the formation and maturation of postnatal testis and secondary reproductive organs leading to male infertility in adult age.
2018-07-01 | GSE89061 | GEO
Project description:It has long been recognized that there is substantial inter-individual variability in the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), but the mechanisms underlying this variability are not well understood. In order to characterize the factors associated with heterogeneity in response to ibuprofen, we performed functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, biochemical assays, and gene expression analysis in twenty-nine healthy subjects who underwent third molar extraction. Subjects were treated with rapid-acting ibuprofen (400 mg; N=19) or placebo (N=10) in a randomized, double-blind design. Compared to placebo, ibuprofen-treated subjects exhibited greater reduction in pain scores, alterations in CBF in brain regions associated with pain processing, and inhibition of ex vivo COX-1 and COX-2 activity and urinary prostaglandin metabolites (p<0.05). Ibuprofen-treated subjects could be stratified into partial responders (N=9, required rescue medication) and complete responders (N=10, no rescue medication). This variability in analgesic efficacy was not associated with demographic/clinical characteristics, markers of systemic inflammation, or ibuprofen pharmacokinetics. Complete responders exhibited less suppression of urinary prostaglandin metabolites and greater induction of serum tumor necrosis factor-α and interleukin 8, compared to partial responders (p<0.05). Partial responders exhibited more alterations in gene expression in peripheral blood mononuclear cells after surgery, with an enrichment in inflammatory pathways. These findings suggest that activation of the prostanoid biosynthetic pathway and regulation of the inflammatory response to surgery differs between partial and complete responders. Future studies are necessary to elucidate the molecular mechanisms underlying this variability and identify biomarkers that are predictive of ibuprofen response.
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Project description:Despite diverging levels of amyloid-β (Aβ) and TAU pathology, different mouse models, as well as sporadic AD patients show predictable patterns of episodic memory loss. MiRNA deregulation is well established in AD brain but it is unclear whether Aβ or Tau pathology drives those alterations and whether miRNA changes contribute to cognitive decline. Therefore miRNAseq was performed on the hippocampus of APPswe/PS1L166P and Thy-TAU22 mice and their respective wild-type littermates when they were cognitively intact (4 months) and impaired (10 months). We found 6 miRNAs that are commonly upregulated between APPtg and TAUtg mice, and four of these were also altered in AD patients. All 6 miRNAs are strongly enriched in neurons as verified by in situ hybridization.
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Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common pharmaceutical agents in the world. However, despite well-studied interactions with cyclooxygenase-2, little is known about the broader proteomic interactions and additional mechanisms that the NSAIDs elicit. Here we present a global binding site identification platform for the direct in cellulo characterization of NSAID binding sites. The platform uses (1) photochemical conjugation of NSAID derivatives in the whole proteome, (2) enrichment of the binding sides, for (3) targeted mass spectrometry-based assignment. Using our approach, we identified the NSAID “interactome” consisting of nearly 200 binding sites in Jurkat and K562 cells. We observed a binding site hotspot on the nucleosome where three NSAIDs (but not fragment-based small molecules) interacted. These data suggest that the NSAIDs may behave as a novel type of epigenetic mark. Our approach is potentially amenable to production of precise, whole proteome binding site maps for virtually any molecule of interest.
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Project description:Ibuprofen is one of the most commonly detected pharmaceuticals in wastewater effluent; however the effects of ibuprofen on aquatic organisms are poorly understood. This study presents the transcriptome-wide response of the inland silverside, Menidia beryllina, to chronic 14 d exposures to ibuprofen.
2015-09-01 | GSE64967 | GEO
Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a progressive cognitive decline. Epidemiological studies have suggested a protective role of caffeine consumption against age-related cognitive impairments and the risk of developing AD. Effects of caffeine have been particularly ascribed to its ability to block adenosine A2A receptors (A2ARs). Early pathological upregulation of these receptors by neurons is thought to be involved in the development of synaptic and memory deficits in AD but this remains ill-defined. To tackle this question, we employed a novel transgenic mouse model allowing to promote a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice, developing AD-like amyloidogenesis. This new model was used to determine the impact of an early upregulation of A2AR on the progression of neuropathological lesions, associated behavior and underlying mechanisms in APP/PS1 mice. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioral changes were not linked to major change in the development of amyloid pathology but rather associate with an increased p-tau at neuritic plaques. Moreover, proteomic and transcriptomic analysis coupled to quantitative immunofluorescence studies indicated that neuronal impairment of the receptor promoted both neuronal- and non-neuronal autonomous alterations i.e. loss of excitatory synapses and neuroinflammatory response, respectively, both presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction as seen in the brain of patients contributes to AD pathogenesis, favoring synaptic deficits promoted by both amyloid (this study) and tau lesions (our previous study). In addition to provide new insights into the complex pathophysiology of AD, the present findings underscore the potential of A2AR as a relevant therapeutic target for mitigating early synaptic loss in this neurodegenerative disorder.
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