Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide

A dual-action cyclooxygenase (COX)–fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX-inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (1), 2-(4-Isobutylphenyl)-N-(2-(3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (9) and N-(3-methylpyridin-2-yl)-2-(4′-isobutylphenyl)propionamide (2) inhibited FAAH with IC50 values of 134, 3.6 and 0.52 µM respectively. The corresponding values for COX-1 were ~29, ~50 and ~60 µM, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC50 values of ~6, ~10 and ~19 µM, respectively. Compound 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists. Read More: http://informahealthcare.com/doi/abs/10.3109/14756366.2011.64330

The transcription T-bet is required for optimal proinflammatory trafficking of CD4+ T cells

Background: The transcription factor T-bet is a critical regulator of Th1 effector function. Animals deficient in T-bet are protected from a variety of inflammatory diseases, including systemic lupus erythematosus and inflammatory arthritis. An essential function of Th1 cells is the ability to traffic appropriately to sites of inflammation, which is largely dependent on the expression of specific selectin ligands and chemokine receptors. We therefore hypothesised that T-bet would modulate lymphocyte trafficking in vitro and in vivo by direct regulation of both selectin binding and chemokine function. Methods: Balb/c mice deficient in, or transgenic for, T-bet had been generated previously. T-bet$^{-/-}$ × DO11.10 TCR and T-bet$^{-/-}$ × IFN$^{-/-}$ mice were generated by backcrossing for >10 generations. CD4$^+$ T cells were generated from primary lymph nodes from all these mice by positive selection and stimulation with appropriate antigen. Functional analysis used the following four methods: adoptive transfer into WT Balb/c mice, which were then injected with OVA, cells were harvested from the spleen, lymph node and peritoneum; selectin binding, interactions with immoblised P-selectin and E-selectin under conditions of laminar flow were examined in a parallel plate flow chamber; expression of selectin ligands, using flow cytometry, real-time PCR and 35S incorporation; and chemokine receptor expression and function, using flow cytometry, real-time PCR, transwell chemotaxis and endothelial binding under flow conditions. Results: Selective migration of T-bet$^{-/-}$ CD4$^+$ T cells in a Th1-dependent model of peritoneal inflammation was completely abrogated. Further investigation revealed that this effect was due to a 50% reduction in binding to P-selectin but not E-selectin under in vitro flow conditions and that this was as a result of impaired tyrosine sulfation of PSGL-1. In addition, mRNA and surface expression of CXCR3, but not CCR5, was reduced and this was associated with a reduction in both transwell chemotaxis and binding to endothelial cells. Retroviral transfer experiments of T-bet cDNA into T-bet$^{-/-}$ and T-bet$^{-/-}$ × IFN$^{-/-}$ cells demonstrated that these effects were independent of interferon. Conclusions: These data establish that T-bet imprints a specific migratory program onto developing CD4$^+$ cells via control of PSGL-1 sulfation (and thus P-selectin binding) and CXCR3 expression and function. Furthermore, as E-selectin and CCR5 binding are unimpaired, this reveals a level of control on trafficking of Th1 lymphocytes not recognised by previous paradigms

Dynamic regulation of the endocannabinoid system: implications for analgesia

The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics

N-Oleoyl-glycine reduces nicotine reward and withdrawal in mice.

Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction

Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

Abstract Background Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs) are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated. Results Intracerebroventricular (icv) administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs) and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than 2 weeks, and it also impaired the analgesic effects of cannabinoids. Conclusion In the brain, cannabinoids can produce analgesic tolerance that is not associated with the loss of surface CB1Rs or their uncoupling from regulated transduction. Neural specific Gz proteins are essential mediators of the analgesic effects of supraspinal CB1R agonists and morphine. These Gz proteins are also responsible for the long-term analgesic tolerance produced by single doses of these agonists, as well as for the cross-tolerance between CB1Rs and MORs.</p

Underreporting of dietary intake by body mass index in premenopausal women participating in the Healthy Women Study

Underreporting patterns by the level of obesity have not been fully assessed yet. The purpose of this study was to examine the differential underreporting patterns on cardiovascular risk factor, macronutrient, and food group intakes by the level of Body Mass Index (BMI). We analyzed cross-sectional baseline nutritional survey data from the population-based longitudinal study, the Healthy Women Study (HWS) cohort. Study subjects included 538 healthy premenopausal women participating in the HWS. Nutrient and food group intakes were assessed by the one-day 24-hour dietary recall and a semi-quantitative food frequency questionnaire, respectively. The ratio of reported energy intake (EI) to estimated basal metabolic rate (BMR) was used as a measure of relative energy reporting status and categorized into tertiles. Overweight group (BMI≥25kg/m2) had a higher ratio of EI to BMR (EI/BMR) than normal weight group (BMI<25kg/m2). Normal weight and overweight groups showed similar patterns in cardiovascular risk factors, nutrient intake, and food group intake by the EI/BMR. Fat and saturated fat intakes as a nutrient density were positively associated with the EI/BMR. Proportion of women who reported higher consumption (≥4 times/wk) of sugar/candy, cream and red meat groups was greater in higher tertiles of the EI/BMR in both BMI groups. Our findings suggest similar patterns of underreporting of cardiovascular risk factors, and macronutrient and food group intakes in both normal and overweight women

Hyperspectral phasor analysis enables multiplexed 5D in vivo imaging

Time-lapse imaging of multiple labels is challenging for biological imaging as noise, photobleaching and phototoxicity compromise signal quality, while throughput can be limited by processing time. Here, we report software called Hyper-Spectral Phasors (HySP) for denoising and unmixing multiple spectrally overlapping fluorophores in a low signal-to-noise regime with fast analysis. We show that HySP enables unmixing of seven signals in time-lapse imaging of living zebrafish embryos

Cancer and renal insufficiency results of the BIRMA study

Background: Half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed. Methods:Primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006. Results: A total of 1218 patients were included. The prevalence of elevated SCR (1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR90 ml min 1 per 1.73 m 2. In all, 78.6% of treated patients (n1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment. Conclusions: The RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing. © 2010 Cancer Research UK.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats

Rationale Pathological impulsivity is a prominent feature in several psychiatric disorders, but detailed understanding of the specific neuronal processes underlying impulsive behavior is as yet lacking. Objectives As recent findings have suggested involvement of the brain cannabinoid system in impulsivity, the present study aimed at further elucidating the role of cannabinoid CB1 receptor activation in distinct measures of impulsive behavior. Materials and methods The effects of the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716A) and agonist WIN55,212-2 were tested in various measures of impulsive behavior, namely, inhibitory control in a five-choice serial reaction time task (5-CSRTT), impulsive choice in a delayed reward paradigm, and response inhibition in a stop-signal paradigm. Results In the 5-CSRTT, SR141716A dose-dependently improved inhibitory control by decreasing the number of premature responses. Furthermore, SR141716A slightly improved attentional function, increased correct response latency, but did not affect other parameters. The CB1 receptor agonist WIN55,212-2 did not change inhibitory control in the 5-CSRTT and only increased response latencies and errors of omissions. Coadministration of WIN55,212-2 prevented the effects of SR141716A on inhibitory control in the 5-CSRTT. Impulsive choice and response inhibition were not affected by SR141716A at any dose, whereas WIN55,212-2 slightly impaired response inhibition but did not change impulsive choice. Conclusions The present data suggest that particularly the endocannabinoid system seems involved in some measures of impulsivity and provides further evidence for the existence of distinct forms of impulsivity that can be pharmacologically dissociated