RESUMO
Serotonin (5-HT) is an important neurotransmitter and paracrine signaling molecule in the gastrointestinal tract. Two distinct tryptophan hydroxylases (TPH), TPH1 and TPH2, are the rate-limiting enzymes in the 5-HT biosynthesis process. TPH1 expression is mainly limited in the enterochromaffin cells and distributed in peripheries such as the skin and gut, while TPH2 is the predominant isoform in the CNS. In this study, mol002291 was screened as a drug-like compound from the TCM database for the inhibitor of TPH. After the enzymological analysis of mol002291, the analgesic effect of mol002291 was also further investigated in a PI-IBS visceral hyperalgesia rat model. Results from kinetic analysis showed that mol002291 specifically inhibited the TPH1 but did not act on TPH2, and the inhibitory action displayed characteristics of competitive inhibition. In addition, the results from abdominal withdrawal reflex (AWR) tests and electromyography (EMG) recordings showed that mol002291 significantly (p < .05) alleviated the visceral hyperalgesia. This result is entirely consistent with the fact that mol002291 significantly decreased the 5-HT content. These data demonstrated that mol002291 can attenuate visceral hyperalgesia mediated via reducing colonic 5-HT content. More important is that mol002291 could be developed as a novel prodrug and offer therapeutic avenues for the diseases where there is dysregulation of peripheral serotonergic pathways.
Assuntos
Analgésicos/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Pró-Fármacos/química , Triptofano Hidroxilase/antagonistas & inibidores , Analgésicos/metabolismo , Analgésicos/uso terapêutico , Animais , Sítios de Ligação , Domínio Catalítico , Bases de Dados Factuais , Eletromiografia , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Cinética , Masculino , Simulação de Acoplamento Molecular , Pró-Fármacos/metabolismo , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Triptofano Hidroxilase/metabolismoRESUMO
BACKGROUND: Treatment with electroacupuncture (EA) at ST25 and CV12 has a significant analgesic effect on postinflammatory irritable bowel syndrome (PI-IBS) visceral pain. Enterochromaffin (EC) cells and serotonin (5-hydroxytryptamine (5-HT)) are important in the development of visceral hyperalgesia. OBJECTIVE: To investigate the analgesic effect and underlying mechanisms of EA at ST25 and CV12 on the treatment of trinitrobenzene sulfonic acid (TNBS)-induced PI-IBS visceral hyperalgesia in rats. METHODS: After EA at ST25 and CV12, changes in abdominal withdrawal reflex (AWR), electromyography (EMG) recordings, colonic EC cell numbers, and expression of tryptophan hydroxylase (TPH), 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) of TNBS-induced PI-IBS visceral hyperalgesia in rats were examined. RESULTS: The results of AWR tests and EMG recordings indicated a significant analgesic effect of EA stimulation at ST25 and CV12on PI-IBS visceral hyperalgesia (p<0.05). In addition, the increased EC cell numbers and colonic expression of TPH and 5-HT in rats with TNBS-induced PI-IBS visceral hyperalgesia were significantly reduced by EA (p<0.05). CONCLUSIONS: EA stimulation at ST25 and CV12 can attenuate visceral hyperalgesia. This analgesic effect may be mediated via reduction of both colonic EC cell number and 5-HT concentration.