Effect of sumatriptan on acetic acid-induced experimental colitis in rats: a possible role for the 5-HT1B/1D receptors.

Mucosal inflammation in colitis is associated with changes in the intestinal serotonin (5-HT) level. Sumatriptan, a 5-HT1B/1D receptor agonist, has demonstrated anti-inflammatory characteristics. The purpose of this study was to determine the effects of sumatriptan in a rat model of acute experimental colitis and to elucidate the probable participation of presynaptic 5-HT1B/1D receptors. To induce colitis, acetic acid (4%) was injected intrarectally. Treatments were given intraperitoneally (IP) once daily over 3 consecutive days starting 1-h post-induction. Sumatriptan was given at 0.5, 1, 2, and 5 mg/kg. GR-127935, a 5-HT1B/1D receptor antagonist, was injected (0.1 and 0.3 mg/kg) 30 min prior to the most effective dose of sumatriptan (1 mg/kg). On day 4, the colon samples were isolated. Significant enhancements of the tissue tumor necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), microscopic and macroscopic damages, body weight losses, and also reductions in tissue superoxide dismutase (SOD) and 5-HT were observed in colitis rats. On the other hand, sumatriptan at doses 0.5, 1, and 2 mg/kg could diminish pathologic changes in the measured biomarkers, histopathologic damages, and body weight losses. Although GR-127935 at dose 0.3 mg/kg could markedly improve the pathologic indexes, its sub-effective dose (0.1 mg/kg) reversed the protective effect of sumatriptan (1 mg/kg). Moreover, sumatriptan (1 and 5 mg/kg) and GR-127935 (0.3 mg/kg) increased the serotonin level. Post-treatment with low-dose sumatriptan demonstrated a protective impact on this peripheral inflammatory condition. Notably, this protective effect may be mediated, at least in part, through 5-HT1B/1D receptors, as well as anti-inflammatory and anti-oxidative characteristics.

Predictive and prognostic value of TLR9 and NFKBIA gene expression as potential biomarkers for human glioma diagnosis.

BACKGROUND: Malignant gliomas are the most common form of primary intracranial tumors with the highest mortality rates. Various gene alterations are considered as prognostic markers in glioma. But, the relevant molecular mechanisms in this setting are not well-understood. OBJECTIVE: The aim of this study was to assess the association and prognostic value of TLR9 and NFKBIA with clinical significance and also their impact on patient survival in human glioma. METHODS: Expression of TLR9 and NFKBIA mRNA in the tissues was determined by immunohistochemistry and qRT-PCR methods. Kaplan-Meier curves and Cox proportional hazards regression model were used to assess the association of TLR9 and NFKBIA with clinical outcomes of patients. RESULTS: Quantitative real-time PCR analysis showed that TLR9 mRNAs is markedly expressed in glioma tissues than in non-neoplastic tissues (mean±SD: 3.26±0.40 vs. 0.71±0.36, P<0.001). There was also a significant difference between TLR9 mRNAs and high grade glioma (P<0.001).NFKBIA mRNAs was significantly identified in non-neoplastic tissues compared with glioma specimens (mean±SD: 2.76±0.30 vs. 0.94±0.35, P<0.001). Lower levels of NFKBIA mRNA were significantly related to advanced grade of gliomas (P<0.001). Furthermore, Immunoreactivity for high expression of TLR9 was detected in 65% of cases (26/40) that was associated with high grade glioma (P=0.001). No statistically significant correlation was found between TLR9 and other clinical parameters (P>0.05). Immunoreactivity for high expression of NFKBIA was observed in 32.5% (13/40) of cases and NFKBIA expression was decreased in patients with high grad glioma (P=0.014). There was no significant correlation between NFKBIA protein expression and age, sex, and relapse. The Kaplan-Meier analysis indicated that patients with high expression of TLR9 and low expression of NFKBIA are significantly related to poorer OS (P<0.001). In addition, the multivariate Cox regression model revealed that TLR9 and NFKBIA protein expressions (low/high) and tumor grade were potentially an independent predictor of survival in patients (hazard ratio, 2.132, 2.411, 2.13 [95% confidence interval, 1.825-3.782, 1.61-3.231, 1.542-3.92]; P=0.012,P=0.018, P=0.001). CONCLUSION: These data indicate that TLR9 and NFKBIA protein expressions act as independent predictor of survival for the diagnosis of glioma and a prognostic biomarker for those with a tumor at an advanced pathological grade.