Cannabinoid-1 receptor inhibition prevents the reduction of 24-hour energy expenditure with weight loss.

Pharmacologic inhibition of the cannabinoid-1 receptor (CB1R) in rodent models leads to weight loss and time-dependent changes in energy balance. This study evaluated the effects of CB1R inhibition on weight loss, energy expenditure (EE), and food intake (FI) in an obese canine model following 4 weeks of treatment. Eighteen maintenance-fed obese beagles were evenly and randomly allocated to a CB1R inverse agonist (AM251) (2 mg/kg), a 70% food-restricted (FR) diet, or a control group (C). Evaluations included body weight and composition (dual-energy x-ray absorptiometry scan), EE (doubly labeled water), and FI. Change in body mass at week 4 was significantly greater (P < .050) in the AM251 (-1476.7 g) and FR groups (-1100.0 g) than in the C group (-228.3 g). Food intake was decreased from week 2 onward in the FR and AM251 groups (P < .05). Absolute and lean mass-adjusted EEs were decreased only in the FR group (P < .01); EE in the AM251 group was greater (P < .05) than that in the FR group. Pharmacologic inhibition of CB1R in a canine model led to sustained effects on FI and EE. Weight loss was greater with AM251 than could be accounted for by food restriction (∼25%), an effect likely mediated by the EE response to CB1R inhibition.

Alendronate binds to tooth root surfaces and inhibits progression of feline tooth resorption: a pilot proof-of-concept study.

Tissue distribution, bioavailability, and efficacy of alendronate in preventing progression of resorption of teeth were evaluated in cats. [Butyl-4-14C-]-alendronate accumulates on subgingival tooth and alveolar bone surfaces adjacent to vascularized tissue resulting in concentration of the drug around tooth roots. Three cats were treated with a 0.03 mg/kg i.v. bolus of [butyl-4-14C-]-alendronate followed by blood, urine, and feces collection and euthanasia 24-hours later. Drug tissue distribution was accessed by autoradiography and sample combustion. To assess bioavailability, 12 cats were administered alendronate orally (3.0 or 9.0 mg/kg in water or 9.0 mg/kg in tuna water) and urine was collected for 24-hours. In these formulations, alendronate oral bioavailability in cats was approximately 3%. In addition, 10 cats with radiographic evidence of pre-existing tooth resorption (14 affected teeth) were treated with vehicle or 3.0 mg/kg alendronate per os once weekly for 22-weeks and, then, 9.0 mg/kg per os twice weekly for 27-weeks in a random, masked study. Radiographic area of resorption was measured and progression scored every 3 to 4-months. In placebo-treated cats, resorption progressed in five of six teeth (+ 97% average increase in area of resorption), whereas progression of resorption was seen in only three of eight affected teeth in alendronate-treated cats with a -22% average change (decrease) in area (P < 0.01 difference in number of teeth showing progression; P < 0.001 difference in area of resorption). Alendronate accumulated preferentially on subgingival tooth surfaces and adjacent alveolar bone and, at a dose of 9 mg/kg twice weekly, effectively slowed or arrested the progression of resorption.

Differential mass spectrometry of rat plasma reveals proteins that are responsive to 17beta-estradiol and a selective estrogen receptor modulator PPT.

Estrogens are a class of steroid hormones that interact with two related but distinct nuclear receptors, estrogen receptor (ER) alpha and beta. To identify potential ER biomarkers, we profiled the rat plasma glycoproteome after treatment with vehicle or 17beta-estradiol (E2) or an ERalpha-selective agonist PPT by differential mass spectrometry. Our comparative proteomic experiment identifies novel E2- and PPT-responsive proteins, such as serine protease inhibitor family members.

Lack of clinical efficacy of a phosphodiesterase-4 inhibitor for treatment of heaves in horses.

Phosphodiesterase-4 (PDE 4) enzyme inhibitors have been shown to have anti-inflammatory properties in various animal disease processes and therefore could be effective drugs for the treatment of equine airway diseases. The purpose of this study was to evaluate the efficacy and adverse effects of the PDE 4 inhibitor L-826,141 in horses with heaves. In a blinded parallel design, horses with heaves exposed daily to moldy hay were given a placebo for 14 days and then administered either L-826,141 (n = 6; loading dose of 1 mg/kg IV followed by 0.5 mg/kg IV q48h) or dexamethasone (n = 6; 0.04 mg/kg IV q24h) from days 15 to 29 (study 1). Pulmonary function and bronchoalveolar (BAL) cytology were evaluated weekly from baseline (day 0) to 29 days. In study 2, horses were treated with L-826,141 (1.0 mg/kg IV q24h) for 8 days. Although ex vivo lipopolysaccharide-induced tumor necrosis factor (TNF)-alpha and LTB4 production by fresh blood were inhibited up to 90% after repeated administrations of L-826,141, this treatment failed to improve lung function. In contrast, dexamethasone (positive control) treatment resulted in significant improvement in lung mechanics and airway function in all horses. Neither drug had a significant effect on BAL total cell counts and differential cytology. Administration of the PDE 4 inhibitor L-826,141 for up to 14 days to horses with heaves was not associated with an improvement in airway function or inflammation. These findings suggest that the PDE 4 enzyme is not a key mediator of lung inflammation in heaves.

17 Beta-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-beta knockout (BERKO) mice.

RATIONALE: The decrease in levels of estrogens (ER) that occurs in menopause has been correlated with depressive disorders, probably due to ER direct and/or indirect effects in the brain, where these hormones act through both genomic (i.e. interaction as transcription factors with nuclear receptors ER-alpha and ER-beta) and non-genomic (i.e. binding with cell-membrane receptors) mechanisms. With respect to mood related disorders the interaction between ER-beta and the serotonin (5-HT) system is highly relevant. 17beta-Estradiol (E2) induces expression of the enzyme implicated in 5-HT synthesis - tryptophan hydroxylase (TPH), and this effect is mediated through ER-beta located in 5-HT cell bodies of the dorsal raphe nucleus (DRN). OBJECTIVE: The present studies tested the hypothesis that E2 induces antidepressant-like effects in female ovariectomized (OVX) mice, and that expression of ER-beta is mandatory for such effects. METHODS: The Forced Swim Test (FST) was used in three experiments to assess (a) dose response effect of E2 in outbred and inbred mouse strains, (b) length of treatment necessary for effect, (c) and role of ER-beta receptors. RESULTS: E2 (100 or 200 microg/kg), as well as the antidepressant desipramine (DMI), significantly reduced total duration of immobility in the FST in mice from different strains. Four consecutive daily doses (200 microg/kg) were required for such effect, which was absent in mice lacking the gene coding for ER-beta (BERKO mice). CONCLUSION: These data suggest that E2-induced antidepressant-like effects in mice are mediated through activation of ER-beta. They offer preliminary support to the hypothesis that specific compounds acting at ER-beta may influence mood in postmenopausal women.

Comparison of effects of dexamethasone and the leukotriene D4 receptor antagonist L-708,738 on lung function and airway cytologic findings in horses with recurrent airway obstruction.

OBJECTIVE: To evaluate whether the leukotriene (LT) D4 receptor antagonist L-708,738 is therapeutically beneficial in treating horses with recurrent airway obstruction (heaves). ANIMALS: 12 adult horses with heaves and healthy lung lobes from 20 slaughtered horses. PROCEDURE: Lung lobes were used for smooth muscle tension and radioligand binding studies. Horses with heaves were given a placebo for 14 days and administered L-708,738 (n = 6; 2.5 mg/kg PO, q 12 h) or dexamethasone (6; 0.04 mg/kg, IV, q 24 h) from days 14 to 28. Pulmonary function was measured weekly for 36 days, and bronchoalveolar cells were collected on days 0,14, and 29 for cytologic examination. RESULTS: Nanomolar concentrations of L-708,738 were effective at antagonizing LTD4-induced bronchoconstriction and LTD4-receptor binding in lung lobes. Mean peak and trough L708,738 plasma concentrations during the treatment period were 1.54 and 0.28 microM, respectively. On days 21 and 29, lung mechanics were significantly improved in the dexamethasone-treated horses but not in the L-708,738-treated horses. Neither dexamethasone nor L-708,738 had a significant effect on cytologic findings. CONCLUSIONS AND CLINICAL RELEVANCE: L-708,738 was bioavailable after oral administration and sustained concentrations in plasma during the dosing period that exceeded in vitro efficacy values. However, airway function did not improve, suggesting that either drug concentrations in the lungs were subtherapeutic or that cysteinyl LT may not be important mediators of airway inflammation in heaves. Results provide the first evidence of cysteinyl LT1 receptors in airways of horses.