aconitine and Colitis

Ulcerative colitis (UC) involves chronic inflammation of the large intestine. Several agents are used to treat UC, but adverse side effects are remaining problems. We examined the effect of tropisetron as a new type of drug for UC using a dextran sulfate sodium (DSS)-induced model of colitis in mice. We developed a DSS-induced model of colitis and calculated the Disease Activity Index and colon length. We measured myeloperoxidase activity and determined the protein level and mRNA level of cytokines in the colon. DSS-induced colitis was ameliorated by administration of tropisetron and PNU282987. Pre-administration of methyllycaconitine diminished the suppressive effect of tropisetron upon DSS-induced colitis. These findings suggested that α7 nicotinic acetylcholine receptors (α7 nAChRs) were related to the suppressive effect of tropisetron on DSS-induced colitis. Additionally, stimulation of α7 nAChRs decreased the colon level of interleukin-6 and interferon-γ upon DSS administration. Furthermore, stimulation of α7 nAChRs decreased macrophage infiltration, with expression of α7 nAChR increased by DSS administration. These results suggest that the underlying mechanism of this suppressive effect on DSS-induced colitis is via stimulation of α7 nAChRs and involves suppression of expression of pro-inflammatory cytokines. Tropisetron could be a new type of therapeutic agent for UC.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Colitis; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Indoles; Inflammation Mediators; Male; Mice, Inbred ICR; Peroxidase; Tropisetron

In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (α7 nAchR) on dextran sulphate sodium (DSS)-induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective α7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective α7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using α7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; Behavior, Animal; Benzamides; Bridged Bicyclo Compounds; Colitis; Dose-Response Relationship, Drug; Drug Antagonism; Hyperalgesia; Male; Mice; Mice, Inbred Strains; Molecular Targeted Therapy; Nerve Tissue Proteins; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Pain Threshold; Pain, Referred; Random Allocation; Receptors, Nicotinic