Background and purpose: Although CB 1 receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPARa and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection. Experimental approach: Assays of PPARa occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPARa activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPARa gene-disrupted mice. Key results: The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPARa ligand binding domain and to increase PPARa-driven transcriptional activity. The high affinity synthetic CB 1/2 cannabinoid agonist WIN 55212-2 bound to PPARa equipotently with the PPARa agonist fenofibrate, and stimulated PPARa-mediated gene transcription. The phytocannabinoid D 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPARa-null mice. OEA treatment also led to increased expression of the NFkB-inhibitory protein, IkB, in mouse cerebral cortex, while expression of the NFkB-regulated protein COX-2 was inhibited. Conclusions and implications: These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPARa and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.
InVivoStat is a free-to-use statistical software package for analysis of data generated from animal experiments. The package is designed specifically for researchers in the behavioural sciences, where exploiting the experimental design is crucial for reliable statistical analyses. This paper compares the analysis of three experiments conducted using InVivoStat with other widely used statistical packages: SPSS (V19), PRISM (V5), UniStat (V5.6) and Statistica (V9). We show that InVivoStat provides results that are similar to those from the other packages and, in some cases, are more advanced. This investigation provides evidence of further validation of InVivoStat and should strengthen users' confidence in this new software package.
The nuclear transcription factor Fos is inducible by both steroid hormones and peptide growth factors. It thus forms a potential point of interaction between steroid hormone- and growth factor-directed pathways and may be critical in the subversion of steroid hormone control in breast cancer. In this light, the present study has used immunocytochemistry to demonstrate in clinical primary breast cancer that Fos expression is indeed significantly associated with a failure to respond to endocrine therapy, with preliminary analysis revealing a survival advantage for those patients whose tumours lacked Fos. Sustained elevated levels of Fos expression were significantly associated with further factors, notably peptide growth factors and their receptors (e.g., EGFR, TGF alpha), as well as with the proliferation marker Ki-67, which have been linked previously to endocrine insensitivity in breast cancer. In contrast, there appeared to be a trend for Fos to be absent in those tumours expressing markers of endocrine responsiveness (e.g., oestrogen receptor [ER], and also ER-mediated markers i.e., PR, pS2 or bcl-2). Interestingly, many of these trends were maintained in ER+ patients, suggesting that Fos may be of importance in directing loss of endocrine sensitivity in ER+ disease.
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