A Novel Topical PPARγ Agonist Induces PPARγ Activity in Ulcerative Colitis Mucosa and Prevents and Reverses Inflammation in Induced Colitis Models.

Background: Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPARγ agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis.

Methods: Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPARγ-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay).

Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.

Background And Aims: Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury.

Methods: Eight week old Mdr2(-/-) (Abcb4(-/-)) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.

Oral baclofen reduces visceral pain-related pseudo-affective responses to colorectal distension in rats: relation between plasma exposure and efficacy.

Objective: We previously showed that activation of GABA(B) receptors by intravenous baclofen reduces pseudo-affective responses to colorectal distension in rats. Here we evaluate the potential clinical significance of these observations.

Material And Methods: Clinically relevant colorectal distension protocols were used to assess the effects of oral baclofen on visceromotor and autonomic cardiovascular responses in conscious rats.

Occurrence and pharmacological characterization of four human tachykinin NK2 receptor variants.

Tachykinin NK(2) receptor antagonists are potentially beneficial in treating various disorders including irritable bowel syndrome, urinary incontinence, depression and anxiety. The current study evaluates the frequency of single nucleotide polymorphisms (SNPs) in the human NK(2) receptor gene (TACR2). In addition, the potency of the endogenous peptide agonist neurokinin A (NKA), and the small molecule antagonists saredutant (NK(2)-selective) and ZD6021 (pan-NK antagonist) at the various NK(2) receptor protein variants were determined.

Role of tachykinin NK(1) and NK(2) receptors in colonic sensitivity and stress-induced defecation in gerbils.

The pharmacology of tachykinin NK receptors varies greatly among species. The aim of the present study was to assess the role of NK(1) and NK(2) receptors in mediating colorectal distension-evoked nociception and psychological stress-induced defecation in gerbils, a species with human-like NK receptor pharmacology. The effects of the selective NK(1) and NK(2) receptor antagonists, aprepitant and saredutant, on acute (1 h) restraint stress-evoked defecation and plasma adenocorticotropin (ACTH) levels in gerbils were assessed.

Senktide-induced gerbil foot tapping behaviour is blocked by selective tachykinin NK1 and NK3 receptor antagonists.

Intracerebroventricular (i.c.v.

Neurokinin 1 receptor antagonists: correlation between in vitro receptor interaction and in vivo efficacy.

We compared the neurokinin 1 receptor (NK(1)R) antagonists aprepitant, CP-99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], and ZD6021 [3-cyano-N-((2S)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)phenyl]piperidino]butyl)-N-methyl]napthamide]] with respect to receptor interactions and duration of efficacy in vivo. In Ca(2+) mobilization assays (fluorometric imaging plate reader), antagonists were applied to human U373MG cells simultaneously with or 2.5 min before substance P (SP).

Molecular cloning, mutations and effects of NK1 receptor antagonists reveal the human-like pharmacology of gerbil NK1 receptors.

The present study investigates the pharmacology of the cloned neurokinin 1 receptor from the gerbil (gNK(1)R), a species claimed to have human-like NK(1)R (hNK(1)R) pharmacology. The amino acid sequence of NK(1)R was cloned. The hNK(1)R, rat NK(1)R (rNK(1)R), gNK(1)R and mutants of the gNK(1)R were expressed in CHO cells.