DataSheet1_Insights Into Acute and Delayed Cisplatin-Induced Emesis From a Microelectrode Array, Radiotelemetry and Whole-Body Plethysmography Study of Suncus murinus (House Musk Shrew).docx

Purpose: Cancer patients receiving cisplatin therapy often experience side-effects such as nausea and emesis, but current anti-emetic regimens are suboptimal. Thus, to enable the development of efficacious anti-emetic treatments, the mechanisms of cisplatin-induced emesis must be determined. We therefore investigated these mechanisms in Suncus murinus, an insectivore that is capable of vomiting.
Methods: We used a microelectrode array system to examine the effect of cisplatin on the spatiotemporal properties of slow waves in stomach antrum, duodenum, ileum and colon tissues isolated from S. murinus. In addition, we used a multi-wire radiotelemetry system to record conscious animals’ gastric myoelectric activity, core body temperature, blood pressure (BP) and heart rate viability over 96-h periods. Furthermore, we used whole-body plethysmography to simultaneously monitor animals’ respiratory activity. At the end of in vivo experiments, the stomach antrum was collected and immunohistochemistry was performed to identify c-Kit and cluster of differentiation 45 (CD45)-positive cells.
Results: Our acute in vitro studies revealed that cisplatin (1–10 μM) treatment had acute region-dependent effects on pacemaking activity along the gastrointestinal tract, such that the stomach and colon responded oppositely to the duodenum and ileum. S. murinus treated with cisplatin for 90 min had a significantly lower dominant frequency (DF) in the ileum and a longer waveform period in the ileum and colon. Our 96-h recordings showed that cisplatin inhibited food and water intake and caused weight loss during the early and delayed phases. Moreover, cisplatin decreased the DF, increased the percentage power of bradygastria, and evoked a hypothermic response during the acute and delayed phases. Reductions in BP and respiratory rate were also observed. Finally, we demonstrated that treatment with cisplatin caused inflammation in the antrum of the stomach and reduced the density of the interstitial cells of Cajal (ICC).
Conclusion: These studies indicate that cisplatin treatment of S. murinus disrupted ICC networking and viability and also affected general homeostatic mechanisms of the cardiovascular system and gastrointestinal tract. The effect on the gastrointestinal tract appeared to be region-specific. Further investigations are required to comprehensively understand these mechanistic effects of cisplatin and their relationship to emesis.

研究目的：接受顺铂（cisplatin）治疗的癌症患者常出现恶心与呕吐等不良反应，但当前的止吐方案仍欠佳。为开发高效能的止吐治疗手段，明确顺铂诱导呕吐的作用机制至关重要。为此，本研究以具备呕吐能力的食虫目动物臭鼩鼱（Suncus murinus）为模型，对该机制展开探究。
实验方法：本研究采用微电极阵列系统（microelectrode array system），检测顺铂对从臭鼩鼱体内分离的胃窦、十二指肠、回肠及结肠组织慢波的时空特性的影响。此外，通过多线遥测系统（multi-wire radiotelemetry system）记录清醒动物96小时内的胃肌电活动、核心体温、血压（BP）及心率指标。同时，运用整体体积描记法同步监测动物的呼吸活动。体内实验结束后，采集胃窦组织并开展免疫组织化学实验，以鉴定c-Kit阳性细胞与分化簇45（cluster of differentiation 45, CD45）阳性细胞。
实验结果：急性体外实验结果显示，1~10 μM浓度的顺铂处理对胃肠道各节段的起搏活动产生急性区域依赖性影响，胃与结肠的反应模式与十二指肠、回肠恰好相反。经顺铂处理90分钟的臭鼩鼱，其回肠主导频率（DF）显著降低，回肠与结肠的波形周期延长。96小时连续记录结果表明，顺铂在早发相与迟发相均可抑制动物的摄食与饮水行为，引发体重下降。此外，顺铂可降低主导频率、升高胃动过缓的功率占比，并在急性与迟发阶段诱发低温反应；同时还观察到血压与呼吸频率出现降低。最后，本研究证实顺铂处理会引发胃窦炎症，并降低卡哈尔间质细胞（interstitial cells of Cajal, ICC）的密度。
研究结论：本研究结果表明，对臭鼩鼱施以顺铂处理会破坏卡哈尔间质细胞的网络结构与存活状态，同时影响心血管系统与胃肠道的整体稳态调控机制。其对胃肠道的影响呈现区域特异性。未来仍需开展进一步研究，以全面阐明顺铂的上述机制效应及其与呕吐症状的关联。