Abstract
BackgroundPatients receiving anticancer chemotherapy experience a multitude of gastrointestinal side‐effects. However, the causes of these symptoms are uncertain and whether these therapeutics directly affect the enteric nervous system is unknown. Our aim was to determine whether the function and morphology of myenteric neurons are altered in specimens of the colon from chemotherapy‐treated patients.MethodsColon specimens were compared from chemotherapy‐treated and non‐treated patients following colorectal resections for removal of carcinoma. Intracellular electrophysiological recordings from myenteric neurons and immunohistochemistry were performed in whole mount preparations.Key ResultsMyenteric S neurons from chemotherapy‐treated patients were hyperexcitable; more action potentials (11.4 ± 9.4, p < 0.05) were fired in response to depolarising current pulses than in non‐treated patients (1.4 ± 0.5). The rheobase and the threshold to evoke action potentials were significantly lower for neurons from chemotherapy‐treated patients compared to neurons from non‐treated patients (p < 0.01). Fast excitatory postsynaptic potential reversal potential was more positive in neurons from chemotherapy‐treated patients (p < 0.05). An increase in the number of neurons with translocation of Hu protein from the cytoplasm to the nucleus was observed in specimens from chemotherapy‐treated patients (103 ± 25 neurons/mm2, 37.2 ± 7.0%, n = 8) compared to non‐treated (26 ± 5 neurons/mm2, 11.9 ± 2.7%, n = 12, p < 0.01). An increase in the soma size of neuronal nitric oxide synthase‐immunoreactive neurons was also observed in these specimens.Conclusions & InferencesThis is the first study suggesting functional and structural changes in human myenteric neurons in specimens of colon from patients receiving anticancer chemotherapy. These changes may contribute to the causation of gastrointestinal symptoms experienced by chemotherapy‐treated patients.
Highlights
Colorectal cancer (CRC) is the second most commonly diagnosed cancer and is a major cause of cancer-related deaths worldwide
A long after-hyperpolarization was recorded in only one neuron; this neuron had an inflection on the falling phase of its action potential; features identifying it as an AH type II enteric neurons
Due to the scarcity of AH neurons, only S neurons confirmed by the presence of a fast EPSP and uniaxonal morphology were analyzed in this study
Summary
Colorectal cancer (CRC) is the second most commonly diagnosed cancer and is a major cause of cancer-related deaths worldwide. The standard first-line chemotherapy of metastatic CRC is 5-fluorouracil (5-FU) combined with folinic acid plus either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI).[1] these drugs increase survival rate and reduce the risk of disease progression, both have acute and long-term toxicities leading to a wide spectrum of sideeffects. Symptoms such as pain, paresthesia (tingling or numbness), cold-induced dysesthesia (burning sensations), and a general loss of sensation[2,3,4,5,6] have been attributed to peripheral neuropathies resulting from the neurotoxic effects of chemotherapeutic drugs. Our aim was to determine whether the function and morphology of myenteric neurons are altered in specimens of the colon from chemotherapy-treated patients
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