Search

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.

Motility of the gastrointestinal tract (GI) is governed by an bioelectrical event termed slow waves. Accurately measuring the characteristics of GI slow waves is critical to understanding its role in clinical applications. High-resolution (HR) bioelectrical mapping involves placing a spatially dense array of electrodes directly over the surface of the GI wall to record the spatiotemporal changes in slow waves. A micro-electrode array (MEA) with spatial resolution of 200 μm in an 8x8 configuration was employed to record intestinal slow waves using isolated tissues from small animals including rodents, shrews and ferrets. A filtering, processing, and analytic pipeline was developed to extract useful metrics from the recordings. The pipeline relied on CWT and Hilbert Transform to identify the frequency and phase of the signals, from which the individual activation times of slow waves were identified and clustered using k-means. A structural similarity index was applied to group the major activation patterns. Overall, the pipeline identified 91 cycles of slow waves from 300 s of recordings in mice, with an average frequency of 20.68 ± 0.71 cpm, amplitude of 7.94 ± 2.15 µV, and velocity of 3.64 ± 1.75 mm s

Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients’ quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients’ quality of life., HW is supported by Sonata Bis 7 grant no. 2017/26/E/NZ3/00434 from the National Science Centre, Poland and intramural grant no. 1/8971(500) from Military Institute of Medicine. AgB is the recipient of a scholarship from Postgraduate School of Molecular Medicine funded by European Union resources under the European Social Fund - Operational Program Knowledge, Education and Development under the project “Program of Interdisciplinary Doctoral Studies using new generation sequencing (NGS) in personalized medicine”. RA research is supported by Ministerio de Ciencia, Innovación y Universidades, Spain (PID2019-111510RB-I00).