Tropisetron upregulates cannabinoid CB1 receptors in cerebellar granule cells: Possible involvement of calcineurin

被引:25
作者
Rahimian, Reza [1 ]
Dehpour, Ahmad Reza [1 ]
Fakhfouri, Gohar [2 ]
Khorramizadeh, Mohammad Reza [3 ]
Ghia, Jean-Eric [4 ]
Seyedabadi, Mohammad [1 ]
Caldarelli, Antonio [5 ]
Mousavizadeh, Kazem [6 ]
Forouzandeh, Mehdi [7 ]
Mehr, Shahram Ejtemaei [1 ]
机构
[1] Univ Tehran Med Sci, Sch Med, Dept Pharmacol, Tehran, Iran
[2] Shahid Beheshti Univ Med Sci, Sch Med, Dept Pharmacol, Tehran, Iran
[3] Univ Tehran Med Sci, Sch Adv Med Technol, Dept Med Biotechnol, Tehran, Iran
[4] Univ Manitoba, Fac Med, Dept Immunol & Internal Med, Gastroenterol Sect, Winnipeg, MB, Canada
[5] Univ Piemonte Orientale, Dipartimento Sci Chim Alimentari Farmaceut & Farm, Novara, Italy
[6] Univ Tehran Med Sci, Cellular & Mol Res Ctr, Tehran, Iran
[7] Tarbiat Modares Univ, Sch Med Sci, Dept Med Biotechnol, Tehran, Iran
关键词
Tropisetron; Cannabinoid receptor; Cerebellar granule neurons; Calcineurin; 5-HT3; RECEPTORS; EXPRESSION; NEURONS; ANTAGONISTS; COLITIS; RATS; PCR;
D O I
10.1016/j.brainres.2011.08.050
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Tropisetron, a selective 5-HT3 receptor antagonist, is widely used to counteract chemotherapy-induced emesis. Some investigations describe disparate effects including immunomodulatory properties for tropisetron which may be mediated through immunophilin-calcineurin pathway. Calcineurin, a phosphatase involved in immune system signaling, modulates expression of several genes, such as Cannabinoid type one (CB1) receptors. On the quest for its underlying mechanisms of action, this study aimed to investigate the effect of tropisetron on calcineurin activity and CB1, receptor expression and function in cerebellar granule neurons (CGNs). The rat pup CGNs were used as highly calcineurin-rich and devoid of 5-HT3 receptor neuronal cells. Calcineurin activity was assessed in CGNs treated with tropisetron or the congener granisetron at 1 nM-10 mu M concentrations. Moreover, cannabinoid CB1 receptor expression at mRNA and protein levels were investigated by real time PCR and western blotting, respectively and its functionality studied by measuring the secondary messenger CAMP in CGNs receiving tropisetron or granisetron. Results indicate that tropisetron, but not granisetron, significantly inhibits the phosphatase activity of calcineurin, over-expresses the CB1 receptors at both transcriptional and protein levels, and reduces cAMP content. Our investigation shows that tropisetron targets calcineurin in a receptor-independent fashion. Tropisetron-induced CB1 receptor up-regulation might underlie many pharmacological aspects of tropisetron unrelated to anti-emesis. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:1 / 8
页数:8
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