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

Tropisetron, a selective 5-HT(3) 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 (CB(1)) receptors. On the quest for its underlying mechanisms of action, this study aimed to investigate the effect of tropisetron on calcineurin activity and CB(1) receptor expression and function in cerebellar granule neurons (CGNs). The rat pup CGNs were used as highly calcineurin-rich and devoid of 5-HT(3) receptor neuronal cells. Calcineurin activity was assessed in CGNs treated with tropisetron or the congener granisetron at 1nM-10μM concentrations. Moreover, cannabinoid CB(1) 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 CB(1) 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 CB(1) receptor up-regulation might underlie many pharmacological aspects of tropisetron unrelated to anti-emesis.