AIM: To study the effects of entacapone, a catecholO-methyltransferase inhibitor, on colon motility and electrolyte transport in Parkinson's disease(PD) rats.METHODS: Distribution and expression of catecholO-methy...AIM: To study the effects of entacapone, a catecholO-methyltransferase inhibitor, on colon motility and electrolyte transport in Parkinson's disease(PD) rats.METHODS: Distribution and expression of catecholO-methyltransferase(COMT) were measured by immunohistochemistry and Western blotting methods. The colonic smooth muscle motility was examined in vitroby means of a muscle motility recording device. The mucosal electrolyte transport of PD rats was examined by using a short-circuit current(I SC) technique and scanning ion-selective electrode technique(SIET). Intracellular detection of c AMP and c GMP was accomplished by radioimmunoassay testing. RESULTS: COMT was expressed in the colons of both normal and PD rats, mainly on the apical membranes of villi and crypts in the colon. Compared to normal controls, PD rats expressed less COMT. The COMT inhibitor entacapone inhibited contraction of the PD rat longitudinal muscle in a dose-dependent manner. The β2 adrenoceptor antagonist ICI-118,551 blocked this inhibitory effect by approximately 67%(P < 0.01). Entacapone increased mucosal ISC in the colon of rats with PD. This induction was significantly inhibited by apical application of Cl- channel blocker diphenylamine-2, 2'-dicarboxylic acid, basolateral application of Na+-K+-2Cl-co-transporter antagonist bumetanide, elimination of Cl- from the extracellular fluid, as well as pretreatment using adenylate cyclase inhibitor MDL12330 A. As an inhibitor of prostaglandin synthetase, indomethacin can inhibit entacaponeinduced ISC by 45%(P < 0.01). When SIET was applied to measure Cl- flux changes, this provided similar results. Entacapone significantly increased intracellular c AMP content in the colonic mucosa, which was greatly inhibited by indomethacin.CONCLUSION: COMT expression exists in rat colons. The β2 adrenoceptor is involved in the entacaponeinduced inhibition of colon motility. Entacapone induces c AMP-dependent Cl- secretion in the PD rat.展开更多
Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippoca...Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice.To investigate the effects of entacapone,a modulator of dopamine,on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus,60 mice(7 weeks old)were randomly divided into a vehicle-treated group and the groups treated with 10,50,or 200 mg/kg entacapone.The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition.Immunohistochemical staining results revealed that after entacapone treatment,the numbers of Ki67-positive proliferating cells,doublecortin-positive immature neurons,and phosphorylated cAMP response element-binding protein(pCREB)-positive cells were significantly increased.Western blot analysis results revealed that treatment with tyrosine kinase receptor B(TrkB)receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor(BDNF).Entacapone treatment antagonized the effects of TrkB receptor antagonist.These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway.This study was approved by the Institutional Animal Care and Use Committee of Seoul National University(approval No.SNU-130730-1)on February 24,2014.展开更多
基金Supported by National Natural Science Foundation of China,No.81270443,No.81274173 and No.31300954
文摘AIM: To study the effects of entacapone, a catecholO-methyltransferase inhibitor, on colon motility and electrolyte transport in Parkinson's disease(PD) rats.METHODS: Distribution and expression of catecholO-methyltransferase(COMT) were measured by immunohistochemistry and Western blotting methods. The colonic smooth muscle motility was examined in vitroby means of a muscle motility recording device. The mucosal electrolyte transport of PD rats was examined by using a short-circuit current(I SC) technique and scanning ion-selective electrode technique(SIET). Intracellular detection of c AMP and c GMP was accomplished by radioimmunoassay testing. RESULTS: COMT was expressed in the colons of both normal and PD rats, mainly on the apical membranes of villi and crypts in the colon. Compared to normal controls, PD rats expressed less COMT. The COMT inhibitor entacapone inhibited contraction of the PD rat longitudinal muscle in a dose-dependent manner. The β2 adrenoceptor antagonist ICI-118,551 blocked this inhibitory effect by approximately 67%(P < 0.01). Entacapone increased mucosal ISC in the colon of rats with PD. This induction was significantly inhibited by apical application of Cl- channel blocker diphenylamine-2, 2'-dicarboxylic acid, basolateral application of Na+-K+-2Cl-co-transporter antagonist bumetanide, elimination of Cl- from the extracellular fluid, as well as pretreatment using adenylate cyclase inhibitor MDL12330 A. As an inhibitor of prostaglandin synthetase, indomethacin can inhibit entacaponeinduced ISC by 45%(P < 0.01). When SIET was applied to measure Cl- flux changes, this provided similar results. Entacapone significantly increased intracellular c AMP content in the colonic mucosa, which was greatly inhibited by indomethacin.CONCLUSION: COMT expression exists in rat colons. The β2 adrenoceptor is involved in the entacaponeinduced inhibition of colon motility. Entacapone induces c AMP-dependent Cl- secretion in the PD rat.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea Government(MSIP)(NRF-2016R1A2B4009156)the Promising-Pioneering Researcher Program through Seoul National University(SNU)in 2015 and by the Research Institute for Veterinary Science,Seoul National University.
文摘Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice.To investigate the effects of entacapone,a modulator of dopamine,on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus,60 mice(7 weeks old)were randomly divided into a vehicle-treated group and the groups treated with 10,50,or 200 mg/kg entacapone.The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition.Immunohistochemical staining results revealed that after entacapone treatment,the numbers of Ki67-positive proliferating cells,doublecortin-positive immature neurons,and phosphorylated cAMP response element-binding protein(pCREB)-positive cells were significantly increased.Western blot analysis results revealed that treatment with tyrosine kinase receptor B(TrkB)receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor(BDNF).Entacapone treatment antagonized the effects of TrkB receptor antagonist.These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway.This study was approved by the Institutional Animal Care and Use Committee of Seoul National University(approval No.SNU-130730-1)on February 24,2014.
