Phytotherapeutic Approach in the Management of Cisplatin Induced Vomiting; Neurochemical Considerations in Pigeon Vomit Model

Abstract

Cisplatin induced vomiting involves multiple mechanisms in its genesis and a single antiemetic agent do not cover both the phases (acute & delayed) of vomiting in clinics; necessitating the use of antiemetics in combination. Cannabis sativa and other selected plants have ethnopharmacological significance in relieving emesis. The aim of the present study was to investigate the intrinsic antiemetic profile of Cannabis sativa (CS), Bacopa monniera (BM, family Scrophulariaceae), and Zingiber officinale (ZO, family Zingiberaceae) in combinations against vomiting induced by highly emetogenic anticancer drug-cisplatin in pigeons. We have analysed the neurotransmitters which trigger the vomiting response centrally and peripherally. Electrochemical detector (ECD) was used for the quantification of neurotransmitters and their respective metabolites by high performance liquid chromatography in the brain stem (BS) and area postrema (AP) while peripherally in the small intestine. Cisplatin (7 mg/kg i.v.) induced reliable vomiting throughout the observation period (24 hrs). CS-HexFr (10 mg) + BM-MetFr (10 mg)–Combination 1, BM-ButFr (5 mg) + ZO-ActFr (25 mg)–Combination 2, ZO-ActFr (25 mg) + CS-HexFr (10 mg)–Combination 3, and CS-HexFr (10 mg) + BM-ButFr (5 mg)–Combination 4; provided ~30% ( $30\pm 1.1$ ), 70% ( $12\pm 0.4$ ; $P<0.01$ ), 60% ( $19\pm 0.2$ ; $P<0.05$ ) and 90% ( $05\pm 0.1$ ; $P<0.001$ ) protection, respectively, against cisplatin induced vomiting as compared to cisplatin control. Standard MCP (30 mg) provided ~50% ( $23\pm 0.3$ ) protection ( $P>0.05$ ). CS Hexane fraction ( $10\text{mg}/\text{kg}$ ), BM methanolic ( $10\text{mg}/\text{kg}$ ) and bacoside rich $n$ -butanol fraction ( $5\text{mg}/\text{kg}$ ) and ZO acetone fraction ( $25\text{mg}/\text{kg}$ ) alone provided ~62%, 36%, 71%, and 44% protection, respectively, as compared to cisplatin control. The most effective and synergistic combination 4 was found to reduce 5HT and 5HIAA ( $\text{P}<0.05–0.001$ ) in all the brain areas area postrema (AP)+brain stem (BS) and intestine at the 3rd hour of cisplatin administration. In continuation, at the 18th of cisplatin administration reduction in dopamine ( $P<0.001$ ) in the AP and 5HT in the brain stem and intestine ( $P<0.001$ ) was observed. The said combination did not change the neurotransmitters basal levels and their respective metabolites any significantly. In conclusion, all the tested combinations offered protection against cisplatin induced vomiting to variable degrees, where combination 4 provided enhanced attenuation by antiserotonergic mechanism at the 3rd hour while a blended antidopaminergic and antiserotonergic mechanism at the 18th hour after cisplatin administration.