Although neutrophils are strongly implicated in eliminating pathogens, excessive recruitment may cause tissue damage. Therefore, reducing cell influx during an inflammatory process may be a potential target for treating inflammatory bowel diseases (IBD). As CXCR2 is involved in neutrophil migration, this study aimed to evaluate whether the systemic therapeutic treatment with selective CXCR2 antagonist SB225002 ameliorates experimental colitis, which was induced in mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS). After colitis establishment (24 h), mice were treated with SB225002. At later time-points, up to 72 h, mice were monitored for body weight loss and overall mortality. At the time of sacrifice, colonic tissues were scored for macro- and microscopic damage, and cytokine levels, myeloperoxidase (MPO) activity, and protein expression were analyzed. TNBS administration induced macro- and microscopic damage in colon tissue, leading in most cases to animal death. Curative treatment with SB225002 significantly reduced all of the parameters analyzed, leading to an improvement of inflammatory signs. SB225002 reduced neutrophil influx, MPO activity, IL-1beta, MIP-2, and keratinocyte-derived chemokine (KC) levels and the expression of vascular endothelial growth factor, inducible NO synthase, and cyclooxygenase-2 proteins into the colon tissue. Levels of IL-4 and IL-10 were increased significantly in the colons of animals treated with SB225002. Additionally, curative treatment with mouse anti-KC significantly reduced MPO activity and colonic damage. These results taken together demonstrate that a selective blockade of CXCR2 consistently reduced TNBS-induced colitis, suggesting that the use of SB225002 is a potential therapeutic approach for the treatment of IBD and other related inflammatory disorders.

Background and purpose: Kinins are implicated in many pathophysiological conditions, and recent evidence has suggested their involvement in colitis. This study assessed the role of the kinin B 1 receptors in a mouse model of colitis. Experimental approach: Colitis was induced in mice by 2,4,6-trinitrobenzene sulphonic acid (TNBS), and tissue damage and myeloperoxidase activity were assessed. B 1 receptor induction was analysed by organ bath studies, binding assay and reverse transcription PCR. Key results: TNBS-induced colitis was associated with tissue damage, neutrophil infiltration and time-dependent increase of colon B 1 receptor-mediated contraction, with the maximal response observed at 72 h. The upregulation of the B 1 receptor at this time point was also confirmed by means of binding studies. B 1 receptor mRNA levels were elevated as early as 6 h after colitis induction and remained high for up to 48 h. TNBS-evoked tissue damage and neutrophil influx were reduced by the selective B 1 receptor antagonist SSR240612, and in B 1 receptor knockout mice. In vivo treatment with inhibitors of protein synthesis, nuclear factor-kB activation, inducible nitric oxide synthase (iNOS) or tumour necrosis factor a (TNFa) significantly reduced B 1 receptor agonist-induced contraction. Similar results were observed in iNOS and TNF receptor 1-knockout mice. Conclusions and implications: These results provide convincing evidence on the role of B 1 receptors in the pathogenesis of colitis. Therefore, the blockade of kinin B 1 receptors might represent a new therapeutic option for treating inflammatory bowel diseases.

These results demonstrate that ET-1 evokes pruritic and nociceptive behaviors in the mouse cheek model. Both responses to ET-1 appear to be mediated via ET(A) receptors and subjected to limitation by simultaneous ET(B) receptor activation. Local endogenous opioids acting on μ-opioid receptors selectively modulate the pruritic response to ET-1, whereas histamine, possibly derived from mast cells and acting on H(1) receptors, contributes importantly to the nociceptive effect of ET-1 in this model.

No abstract

The factors that trigger the pathophysiology of Parkinson's disease (PD) are unknown. However, it is suggested that environmental factors, such as exposure to pesticides, play an important role, in addition to genetic predisposition and aging. Early signs of PD can appear in the gastrointestinal (GI) tract and in the olfactory system, preceding the onset of motor impairments by many years. The present study assessed the effects of oral rotenone administration (30 mg/kg) in inducing GI and olfactory dysfunctions associated with PD in mice. Here we show that rotenone transiently increased myeloperoxidase activity within 24 h of administration. Leucocyte infiltration in the colon, associated with histological damage and disrupted GI motility, were observed following treatment with rotenone for 7 days. Moreover, 7 days of treatment with rotenone disrupted olfactory discrimination in mice without affecting social recognition ability. The presence of specific deficits in olfactory function occurred with a concomitant decrease in tyrosine hydroxylase-positive neurons and an increase in serotonin (5-hydroxytryptamine) turnover in the olfactory bulb. These findings suggest that in Swiss mice, exposure to rotenone induces GI and olfactory dysfunction involving immunological and neurotransmitter alterations, similar to early signs of PD. This provides further evidence for the involvement of the gut-brain axis in PD.