Analgesic and Anti-Inflammatory Effects of Monoacylglycerol Lipase Inhibition in Mice Subjected to Collagen-Induced Arthritis

Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory joint disease, affecting approximately 1% of the world population. This autoimmune disease is characterized by pain, stiffness, swelling, and breakdown of cartilage in synovial joints. Current RA analgesic treatments (i.e., pain reducing drugs) are ineffective or induce negative side effects, and so there are many concerted efforts to discover new RA treatments. Cannabinoids have analgesic and anti-inflammatory properties; however, the challenge remains to harness the medical potential of cannabinoids without inducing negative psychoactive effects (e.g., cognitive deficits, emotional disruption, and abuse potential). An alternative approach focuses on the endogenously produced cannabinoids (endocannabinoids). The endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide are catabolized by the enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. Pharmacological inhibition of MAGL or FAAH increases brain levels of the respective endocannabinoids, 2-AG or anandamide, and significantly decreases inflammatory pain. The present study tested the hypothesis that MAGL inhibition decreases hyperalgesia, locomotor suppression, and allodynia caused by collagen-induced arthritis (CIA), a well-established animal model of inflammatory arthritis. Separate groups of mice subjected to CIA were administered acute or chronic doses of the selective MAGL inhibitor JZL184 and tested for (1) thermal hyperalgesia in the hotplate and tail immersion tests, (2) mechanical allodynia, and (3) suppressed locomotor activity. Thermal hyperalgesia was significantly attenuated by acute JZL184 (8 or 40 mg/kg) in the hot plate test, but not the tail immersion test. The lack of JZL184 attenuation of hyperalgesia in the tail immersion test may indicate a JZL184 supraspinal mechanism of action. Although the present study was hampered by ongoing model development, these results suggest that MAGL inhibition may be a promising strategy for the treatment of pain caused by inflammatory arthritis

Inhibiting the Cannabinoid Catabolic Enzyme MAGL to Potentiate the Anti-Arthritic Properties of the Synthetic Glucocorticoid Dexamethasone

Rheumatoid arthritis (RA, Table 1) is the most common type of inflammatory arthritis, and is characterized by swelling, inflammation, pain, and destruction of the synovial joints (i.e., knees, elbows, wrists, hips, and fingers). Glucocorticoid receptor agonists are a type of steroid hormone and are among the most common treatments for inflammatory arthritis because of their powerful anti-inflammatory effects. However, harmful side effects are associated with these glucocorticoids (GCs), including increasing patients\u27 vulnerability to infections. Cannabinoids (i.e., cannabis-like signaling molecules) exert anti-inflammatory and analgesic effects with limited side effects compared to traditional immunosuppressants making them excellent targets for the development of new arthritic therapeutics. For example, in mice, selective inhibition of the cannabinoid enzyme monoacylglycerol lipase (MAGL) reduces acute inflammatory pain and edema. Dual administration of drugs are promising novel treatments because it allows lower doses of drugs to attenuate pain and inflammation, while limiting side effects. Combined administration of an endocannabinoid enzyme inhibitor and nonsteroidal anti-inflammatory drug reduces neuropathic and acute pain. Similarly, inflammatory arthritis is reduced by a GC administered with an anti-inflammatory cytokine (i.e., immune system signaling molecule) in mice. Given the anti-inflammatory properties of MAGL inhibition, it is plausible that MAGL inhibition will increase the analgesic and anti-inflammatory effects of a steroid treatment, perhaps reducing the negative side effects of the steroid. Therefore, the goals of the present studies were to determine the analgesic and anti-inflammatory efficacy of (1) the MAGL inhibitor JZL184; (2) the glucocorticoid steroid dexamethasone (DEX); and (3) the combined administration of both JZL184 and DEX. To these ends, we used the collagen-induced arthritis (CIA) mouse model. We found that, although both JZL184 and DEX significantly attenuated proinflammatory cytokine levels in the paws of CIA mice, only DEX decreased pain-related behaviors and paw swelling. Combined administration of a sub-effective dose both drugs was ineffective overall

Insulin-like growth factor I is an independent coregulatory modulator of natural killer (NK) cell activity.

We aimed to investigate the natural killer (NK) cell activity in hGH-deficient adults and to analyze the effect of insulin-like growth factor (IGF)-I in uivo and in vitro on NK cell activity. NK cell activity was measured in a 4-h nonisotopic assay with europium-labeled and cryopreserved K-562 cells. NK-cell numbers were measured after incubation with murine monoclonal CD3 and CD16 antibodies by flow cytometry analysis. In a cross-sectional study, the basal and interferon- p (IFN-P) stimulated (1000 IU/ml) NK cell activity of 15 hGHdeficient patients and 15 age- and sex-matched controls was measured. The percentages and absolute numbers of CD3./16+ NK-cells were not significantly different in the patient vs. control group. The basal and IFN-P stimulated NK cell activity however was significantly decreased in the patient vs. control group at all effecter/target (E/T) cell ratios from 12.5-100 (e.g. 17 ? 3 vs. 28 ? 3% lysis without IFN-P, P < 0.05, and 42 t 4 vs. 57 2 4% lysis with IFN-0, P < 0.05; both at E/T 50). IGF-I levels of patients and controls showed a significant positive correlation with NK cell activity (r = 0.37; P < 0.05). In an IGF-I in vitro study (IGF-I in vitro 250-1250 kg/L), the basal and IFN-P stimulated NK cell activity of 13 hGH-deficient patients and of 18 normal subjects was significantly enhanced by IGF-I in vitro (e.g. GH-deficient patients: 9 ? 2 us. 10 2 2% lysis without IFN-P, P < 0.05 and 25 + 4 vs. 30 + 4% lysis with IFN-/3, P < 0.005; and normal subjects: 15 + 3 vs. 23 ? 3% lysis without IFN-/3, P < 0.001 and 35 2 4 us. 44 + 5% lysis with IFN-P, P < 0.001; both at IGF-I 500 pg/L). In summary, in our cross-sectional study, adult GH-deficient patients showed a significantly lower basal and IFN-P stimulated NK cell activity than matched controls, despite equal NK cell numbers. IGF-I levels of patients and controls showed a weak positive correlation with NK cell activity. In an in vitro study, IGF-I significantly enhanced basal and IFN-P stimulated NK cell activity of hGH-deficient patients and also of normal subjects. The decreased NK cell activity in GHdeficient patients may be caused at least in part by low serum IGF-I levels. IGF-I appears to be an independent coregulatory modulator of NK cell activity. (Endocrinology 137: 5332-5336, 1996

Polynomial Chaos Expansion method as a tool to evaluate and quantify field homogeneities of a novel waveguide RF Wien Filter

For the measurement of the electric dipole moment of protons and deuterons, a novel waveguide RF Wien filter has been designed and will soon be integrated at the COoler SYnchrotron at J\"ulich. The device operates at the harmonic frequencies of the spin motion. It is based on a waveguide structure that is capable of fulfilling the Wien filter condition ($\vec{E} \perp \vec{B}$) \textit{by design}. The full-wave calculations demonstrated that the waveguide RF Wien filter is able to generate high-quality RF electric and magnetic fields. In reality, mechanical tolerances and misalignments decrease the simulated field quality, and it is therefore important to consider them in the simulations. In particular, for the electric dipole moment measurement, it is important to quantify the field errors systematically. Since Monte-Carlo simulations are computationally very expensive, we discuss here an efficient surrogate modeling scheme based on the Polynomial Chaos Expansion method to compute the field quality in the presence of tolerances and misalignments and subsequently to perform the sensitivity analysis at zero additional computational cost.Comment: 12 pages, 19 figure

Electromagnetic Simulation and Design of a Novel Waveguide RF Wien Filter for Electric Dipole Moment Measurements of Protons and Deuterons

The conventional Wien filter is a device with orthogonal static magnetic and electric fields, often used for velocity separation of charged particles. Here we describe the electromagnetic design calculations for a novel waveguide RF Wien filter that will be employed to solely manipulate the spins of protons or deuterons at frequencies of about 0.1 to 2 MHz at the COoler SYnchrotron COSY at J\"ulich. The device will be used in a future experiment that aims at measuring the proton and deuteron electric dipole moments, which are expected to be very small. Their determination, however, would have a huge impact on our understanding of the universe.Comment: 10 pages, 10 figures, 4 table

HRSC Mapping Database: A New Tool to Collect and View Available HRSC-Based Geological Maps Worldwide

We present a new online database for quick and easy access to already published HRSC-based geological mappings on Mars