Fujita Shunsuke, Ushio Soichiro, Ozawa Nana, Masuguchi Ken, Kawashiri Takehiro, Oishi Ryozo, Egashira Nobuaki
Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.
PLoS One. 2015 Nov 4;10(11):e0141921. doi: 10.1371/journal.pone.0141921. eCollection 2015.
Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells.
Oxaliplatin (4 mg/kg) was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves.
Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 μg/kg) could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12) cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26) cells or C-26 cell-implanted mice.
These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes.
奥沙利铂已被广泛用作治疗结直肠癌的关键药物；然而，它会导致周围神经病变。艾塞那肽是一种胰高血糖素样肽-1（GLP-1）激动剂，是从回肠L细胞分泌的一种肠促胰岛素类似物，临床上用于治疗2型糖尿病。据报道，GLP-1受体激动剂对中枢和周围神经系统具有神经保护作用。在本研究中，我们研究了艾塞那肽对大鼠和培养细胞中奥沙利铂诱导的神经病变的影响。
每周两次静脉注射奥沙利铂（4mg/kg），持续4周，并使用von Frey试验评估大鼠的机械性异常性疼痛。通过坐骨神经甲苯胺蓝染色评估轴突变性。
重复给予奥沙利铂从第14天到第49天引起机械性异常性疼痛。虽然联合给予缓释艾塞那肽（100μg/kg）不能抑制奥沙利铂诱导的机械性异常性疼痛的发生率，但它促进了奥沙利铂诱导的神经病变的恢复，并伴有轴突变性的修复。在培养的嗜铬细胞瘤12（PC12）细胞中评估神经突生长的抑制情况。艾塞那肽抑制奥沙利铂诱导的神经突变性，但不影响奥沙利铂对培养的PC12细胞的细胞损伤。此外，缓释艾塞那肽对培养的小鼠结肠腺癌26（C-26）细胞或植入C-26细胞的小鼠中奥沙利铂的抗肿瘤活性没有影响。
这些结果表明，艾塞那肽可能有助于治疗2型糖尿病结直肠癌患者中奥沙利铂诱导的周围神经病变。
