Gingerol inhibits cisplatin-induced vomiting by down regulating 5-hydroxytryptamine, dopamine and substance P expression in minks

Abstract

To investigate the antiemetic effect of gingerol and its multi-targets effective mechanism on 5-hydroxytryptamine (5-HT), dopamine (DA) and substance P (SP). The antiemetic effect of gingerol was investigated on a vomiting model of mink induced by cisplatin (7.5 mg . kg(-1), i.p.) in 6 h observation. The levels of 5-HT, DA and distribution of substance P in the area postrema and ileum were measured by high performance liquid chromatography (HPLC) and immunohistochemistry respectively. The frequency of cisplatin induced retching and vomiting was significantly reduced by pretreatment with gingerol in a dose-dependent manner (P<0.05). Cisplatin produced a significant increase in 5-HT and DA levels in the area postrema and ileum of minks (P<0.05), and this increase was significantly inhibited by gingerol in a dose-dependent manner (P<0.05). Substance P-immunoreactive was mainly situated in the mucosa and submucosa of ileum as well as in the neurons of area postrema, and gingerol markedly suppressed the increase immunoreactivity of substance P induced by cisplatin in a dose-dependent manner (P<0.05). Gingerol has good activity against cisplatin-induced emesis in minks possibly by inhibiting central or peripheral increase of 5-HT, DA and substance P.

Plasma pharmacokinetics and tissue and brain distribution of cisplatin in musk shrews

“…Similar to other emesis models, like the ferret [35], we observed substance P immunoreactivity throughout the dorsal vagal complex. In contrast to the reported effect of cisplatin (7.5 mg/kg, ip) to induce an increase in substance P immunoreactivity in the AP of mink by 6 h [18], we did not observe any significant changes in staining in the AP, NTS or DMN of musk shrews, up to 30 mg/kg ip. We also observed no significant difference in substance P immunoreactivity in the spinal cord between saline and cisplatin treated shrews.…”

“…We chose to focus on these areas because they are involved in generating the emetic reflex (hindbrain) and processing of pain signals (spinal cord); cisplatin treatment is known to produce both emesis and pain in patients [e.g., 16]. Substance P is the endogenous ligand for the NK 1 receptor [17], and cisplatin injection was reported to increase substance P immunoreactivity in the area postrema in mink [18]. In addition, we performed histological analysis of kidney toxicity at these timepoints, since renal toxicity is a common and clinically relevant side-effect of cisplatin treatment [19].…”

Ginger (Zingiber officinale) and chemotherapy-induced nausea and vomiting: a systematic literature review

“…Another hypothesis is that ginger competitively interacts with the same receptors that standard anti‐CINV medication acts upon, thereby reducing the binding rate of medications when used in combination . Animal studies support this hypothesis, indicating that gingerols and shoagoals are able to bind to both 5‐HT 3 and substance P receptors, which are the receptors with which medications such as aprepitant and ondansetron interact . It should also be noted that these studies showed that different ginger compounds bound to these receptors with varying strengths and, therefore, different preparations of ginger could exert differing effects on nausea.…”

Ginger and its pungent constituents non‐competitively inhibit activation of human recombinant and native 5‐HT3 receptors of enteric neurons

“…Pungent arylalkanes (gingerols and shogaols) seem to be part of the active principle as they blocked these receptors in the low micromolar range . This is corroborated by studies in which the antiemetic effects of gingerols and shogaols were demonstrated in animal models . On the basis of these facts, we investigated the mode of action of ginger on human 5‐HT 3 receptors as rodents considerably differ from humans with regard to the 5‐HT 3 receptor system .…”