Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study

Abstract

Serotonergic drugs, such as pergolide, have been associated with the development of cardiac valvular myxoid thickening and regurgitation in humans and more recently in rats. These effects are potentially mediated by the 5-hydroxytryptamine (5-HT)(2B) receptor (5-HT(2B)R). Therefore, we sought to determine whether cyproheptadine, a 5-HT(2B)R antagonist, might prevent toxic valvulopathy in an animal model of pergolide-induced valvular heart disease. For this purpose, 50 male Wistar rats received daily intraperitoneal injections of pergolide (0.5 mg/kg, n = 14), pergolide (0.5 mg/kg) combined with cyproheptadine (10 mg/kg, n = 12), cyproheptadine (10 mg/kg, n = 12), or no injections (control, n = 12) for 20 wk. Echocardiography was performed blindly at baseline and at 10 and 20 wk followed by pathology. At baseline, no differences between groups were found with echocardiography. At 20 wk, aortic regurgitation was present in all pergolide-treated animals, whereas it was less frequently observed in the other groups (P < 0.0001). For the other valves, this difference was less pronounced. On histopathology, not only aortic but also mitral valves were thicker, myxoid, and exhibited more 5-HT(2B)R-positive cells in pergolide-treated animals compared with the other groups. Moreover, regurgitant aortic and mitral valves were thicker than nonregurgitant aortic and mitral valves. In conclusion, we found that cyproheptadine prevented pergolide-induced valvulopathy in rats, which was associated with a reduced number of 5-HT(2B)R-positive valvular cells. This may have important clinical implications for the prevention of serotonergic drug-induced valvular heart disease.

Antiserotonergic Properties of Terguride in Blood Vessels, Platelets, and Valvular Interstitial Cells

“…A general consensus has emerged that 5-HT 2B receptor agonism is the most likely cause of fibrotic valvular heart disease (Roth, 2007;Hutcheson et al, 2011). It has been demonstrated that 5-HT and pergolide-induced valvulopathy in the rat can be prevented by terguride and cyproheptadine, respectively (Hauso et al, 2007;Droogmans et al, 2009). Cyproheptadine is an antagonist with 3-fold higher affinity for 5-HT 2A receptors over 5-HT 2B receptors (Bonhaus et al, 1997).…”

Benfluorex (Mediator®) et atteintes valvulaires

“…Un traitement prolongé (cinq mois) par le pergolide comme par la sérotonine induit des lésions valvulaires très proches de celles observées en pathologie humaine tant sur le plan écho-graphique qu'histologique. Sur ce modèle, il a pu être rapporté que l'utilisation d'un antagoniste spécifique des récepteurs 5HT2b, la cyproheptadine, permet de prévenir le développe-ment de la valvulopathie induite par le pergolide [9], ce qui confirme pleinement l'implication de ce sous-type de récep-teurs sérotoninergiques dans l'induction de valvulopathie. On imagine qu'un tel modèle pourrait permettre de prédire le risque de valvulopathie de nouveaux médicaments susceptibles d'interférer avec le système sérotoninergique.…”

Cyproheptadine Enhances the IK of Mouse Cortical Neurons through Sigma-1 Receptor-Mediated Intracellular Signal Pathway

“…CPH is also widely applicable as an H 1 and 5-hydroxytryptamine (5-HT) receptor antagonist for the treatment of allergic reactions, as a prophylactic for migraines and in the symptomatic treatment of metastatic carcinoid syndrome [1]. As a first-generation antihistamine, CPH produces side effects such as sedation and reduced cognitive function [2].…”