Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Sci Rep. 2017 Aug 29;7(1):9661. doi: 10.1038/s41598-017-08891-1.
Oxaliplatin, a chemotherapy medication, causes severe peripheral neuropathy. Although oxaliplatin-induced peripheral neuropathy is a dose-limiting toxicity, a therapeutic strategy against its effects has not been established. We previously reported the involvement of N-methyl-D-aspartate receptors and their intracellular signalling pathway in oxaliplatin-induced mechanical allodynia in rats. The aim of this study was to clarify the involvement of spinal glutamate transmission in oxaliplatin-induced mechanical allodynia. In vivo spinal microdialysis revealed that the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation of the hind paw markedly increased extracellular glutamate concentration in the same rats. In these rats, the expression of glutamate transporter 1 (GLT-1), which plays a major role in glutamate uptake, was decreased in the spinal cord. Moreover, we explored the potential of pharmacological therapy targeting maintenance of extracellular glutamate homeostasis. The administration of riluzole, an approved drug for amyotrophic lateral sclerosis, suppressed the increase of glutamate concentration, the decrease of GLT-1 expression and the development of mechanical allodynia. These results suggest that oxaliplatin disrupts the extracellular glutamate homeostasis in the spinal cord, which may result in neuropathic symptoms, and support the use of riluzole for prophylaxis of oxaliplatin-induced mechanical allodynia.
奥沙利铂是一种化疗药物，会导致严重的周围神经病变。虽然奥沙利铂引起的周围神经病变是一种剂量限制毒性，但针对其影响的治疗策略尚未建立。我们之前曾报道过 N-甲基-D-天冬氨酸受体及其细胞内信号通路参与奥沙利铂诱导的大鼠机械性痛觉过敏。本研究的目的是阐明脊髓谷氨酸传递在奥沙利铂诱导的机械性痛觉过敏中的作用。体内脊髓微透析显示，奥沙利铂处理的大鼠脊髓中的基础谷氨酸浓度升高，而同样的大鼠足底机械刺激显著增加了细胞外谷氨酸浓度。在这些大鼠中，发挥主要谷氨酸摄取作用的谷氨酸转运体 1 (GLT-1) 的表达在脊髓中减少。此外，我们还探讨了靶向维持细胞外谷氨酸稳态的药物治疗的潜力。批准用于肌萎缩侧索硬化症的利鲁唑的给药抑制了谷氨酸浓度的增加、GLT-1 表达的减少和机械性痛觉过敏的发展。这些结果表明，奥沙利铂破坏了脊髓中的细胞外谷氨酸稳态，这可能导致神经病理性症状，并支持使用利鲁唑预防奥沙利铂引起的机械性痛觉过敏。
