Tranexamic acid induces kaolin intake stimulating a pathway involving tachykinin neurokinin 1 receptors in rats

Abstract

Tranexamic acid suppresses post-partum haemorrhage and idiopathic menorrhagia through its anti-fibrinolytic action. Although it is clinically useful, it is associated with high risks of side effects such as emesis. Understanding the mechanisms underlying tranexamic acid-induced emesis is very important to explore appropriate anti-emetic drugs for the prevention and/or suppression of emesis. In this study, we examined the receptors involved in tranexamic acid-induced kaolin intake in rats, which reflects the drug's clinical emetogenic potential in humans. Further, we examined the brain regions activated by administration of tranexamic acid and elucidated pivotal pathways of tranexamic acid-induced kaolin intake. We examined the effects of ondansetron, a 5-hydroxytryptamine 3 receptor antagonist, domperidone, a dopamine 2 receptor antagonist, and aprepitant, a tachykinin neurokinin 1 (NK₁) receptor antagonist, on tranexamic acid-induced kaolin intake in rats. Then, we determined the brain regions that showed increased numbers of c-Fos immunoreactive cells. Finally, we examined the effects of an antagonist(s) that reduced tranexamic acid-induced kaolin intake on the increase in c-Fos immunoreactive cells. Aprepitant significantly decreased tranexamic acid-induced kaolin intake. However, neither ondansetron nor domperidone decreased kaolin intake. Tranexamic acid significantly increased c-Fos immunoreactive cells by approximately 5.5-fold and 22-fold in the area postrema and nucleus of solitary tract, respectively. Aprepitant decreased the number of c-Fos immunoreactive cells in both areas. Tranexamic acid induced kaolin intake possibly via stimulation of tachykinin NK₁ receptors in rats. The tachykinin NK₁ receptor could be targeted to prevent and/or suppress emesis in patients receiving tranexamic acid.

Introduction

Tranexamic acid, a low molecular weight lysine analogue, exerts its anti-fibrinolytic action by blocking the binding of lysine to plasminogen that plays an important role in fibrin degradation (Wellington and Wagstaff, 2003). Tranexamic acid suppresses traumatic hyphaema, gastrointestinal bleeding and hereditary angioneurotic oedema (McCormack, 2012). The prediction of pharmacoeconomic analyses was that use of tranexamic acid in surgery and trauma would be very cost-effective and potentially life-saving (McCormack, 2012). Although tranexamic acid is a very useful drug, patients receiving tranexamic acid often have nausea (Dunn and Goa, 1999). Tranexamic acid effectively reduced post-partum haemorrhage, which is a serious cause of maternal death worldwide. However, patients receiving tranexamic acid had a higher risk of nausea than control patients (Ferrer et al., 2009). Women with idiopathic menorrhagia were satisfied with tranexamic acid because it decreased or strongly decreased menstrual blood loss. Tranexamic acid mainly has gastrointestinal side effects, including nausea and vomiting (Wellington and Wagstaff, 2003). Understanding the mechanisms underlying tranexamic acid-induced emesis is very important to explore appropriate anti-emetic drugs for prevention and/or suppression of emesis.

Cisplatin, a drug widely used for malignancies, causes acute and delayed emesis (Hainsworth and Hesketh, 1992, Martin, 1996). Ondansetron and granisetron, antagonists of 5-hydroxytryptamine (serotonin) 3 (5-HT₃) receptors, and aprepitant, a tachykinin neurokinin 1 (NK₁) receptor antagonist, prevent emesis induced by cisplatin in humans (Ruff et al., 1994, Navari et al., 1999). Therefore, stimulation of 5-HT₃ and tachykinin NK₁ receptors is thought to play an important role in cisplatin-induced emesis. Some studies indicate that emesis is a side effect of apomorphine, which is used to treat patients with addiction and Parkinson's disease (Ribarič, 2012, Heaton et al., 1995, Corsini et al., 1976). Domperidone, a dopamine 2 (D₂) receptor antagonist, inhibits the apomorphine-induced emesis (Takeda et al., 1993), which suggests that the pathway involving activation of D₂ receptors may be involved in apomorphine-induced emesis.

Intake of kaolin, a white clay composed of silicate minerals, has been a good index to predict emetic liability of compounds such as cisplatin, apomorphine, cyclophosphamide, lithium chloride, nicotine, morphine, rolipram, copper sulphate, and cholecystokinin octapeptide in rats (Percie du Sert et al., 2012). Yamamoto et al. (2007) have reported that kaolin intake induced by anti-cancer drugs in rats is related to the clinical emetogenic potential of these drugs. Antagonists of 5-HT₃ and tachykinin NK₁ receptors, including ondansetron and aprepitant, respectively, reduce cisplatin-induced kaolin intake in rats (Malik et al., 2007, Saeki et al., 2001, Takeda et al., 1993, Tatsushima et al., 2011). Similarly, apomorphine-induced kaolin intake is inhibited by domperidone in rats (Takeda et al., 1993). These findings suggest that pathways that stimulate 5-HT₃, tachykinin NK₁ and D₂ receptors may play pivotal roles in exerting the emetic effect and this effect could be evaluated by measuring kaolin intake in rats.

The proto-oncogene c-Fos has been used as a marker of neuronal activity (Greenberg et al., 1986), and to date, immunohistochemical examination of c-Fos remains one of the most suitable methods to examine the active brain areas in experimental animals. After administration of cisplatin to rats, the number of c-Fos immunoreactive cells markedly increased in the area postrema (AP) and nucleus of solitary tract (NTS), suggesting that activation of these areas may be closely related to kaolin intake (Horn et al., 2007).

In this study, we initially established a method to show that tranexamic acid stably induced kaolin intake in rats. Then, we examined which receptors were involved in tranexamic acid-induced kaolin intake using ondansetron, domperidone and aprepitant. Finally, we examined the brain areas that showed a clear increase in the number of c-Fos immunoreactive cells and elucidated pivotal pathways underlying tranexamic acid-induced kaolin intake.