From the Department of Anesthesiology (S.T., N.S., M.S.) and Department of Pathology (Y.I., T.K.), Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan; Division of Palliative Medicine, Department of Anesthesiology (N.S.), Jikei Medical University Hospital, Tokyo, Japan; and Department of Pharmacology (H.H.S.), Weill Cornell Medical College, New York, New York.
Anesthesiology. 2014 Feb;120(2):459-73. doi: 10.1097/01.anes.0000435634.34709.65.
Oxaliplatin, a chemotherapeutic agent used for the treatment of colorectal cancer, induces dose-limiting neuropathy that compromises quality of life. This study aimed to reproduce, in mice, patients' symptoms of oxaliplatin-induced neuropathy and to observe effects of SS-31, a mitochondria-targeted antioxidant on the neuropathy.
Neuropathy was induced by single or repeated injections of oxaliplatin. Cold and mechanical hypersensitivities were assessed by 15°C-cold plate, temperature preference, and von Frey tests. Morphology of peripheral nerves and dorsal root ganglions, expression of spinal cord c-Fos, density of intraepidermal nerve fibers, and levels of dorsal root ganglion-reactive oxygen/nitrogen species were examined. SS-31 was administered concomitantly or after oxaliplatin injections.
Single injection of oxaliplatin induced cold hypersensitivity in forepaws but not in hind paws which resolved within days (maximal forepaw shakes: 28 ± 1.5 vs. 9.3 ± 1.6/150 s, mean ± SEM, P < 0.001, n = 6 per group). Oxaliplatin-administered mice disfavored 10° and 15°C plates more than control. Paw stimulation at 15°C induced c-Fos-positive cells within superficial laminae of the dorsal horn in C7-T1 segments. Weekly administrations induced gradual development of persistent mechanical allodynia in the hind paws (minimal mechanical threshold: 0.19 ± 0.08 vs. 0.93 ± 0.11 g, P < 0.001, n = 10 per group). Microscopy revealed no overt morphological changes in peripheral nerves and dorsal root ganglions. Concomitant SS-31 administration with repeated oxaliplatin administration attenuated both cold and mechanical hypersensitivity. Decrease in intraepidermal nerve fibers and increase in dorsal root ganglion-reactive oxygen/nitrogen species were also attenuated. Acute SS-31 administration after symptoms were established reversed only cold hypersensitivity.
This model of oxaliplatin-induced neuropathy mimicked patients' conditions. SS-31 has potentials to prevent both acute and chronic neuropathies but is only helpful in treatment of acute neuropathy. (Anesthesiology 2014; 120:459-73).
奥沙利铂是一种用于治疗结直肠癌的化疗药物，会引起剂量限制的周围神经病变，从而降低生活质量。本研究旨在通过单次或重复注射奥沙利铂，在小鼠中再现患者的奥沙利铂诱导的周围神经病变症状，并观察线粒体靶向抗氧化剂 SS-31 对神经病变的影响。
通过单次或重复注射奥沙利铂诱导周围神经病变。通过 15°C 冷板、温度偏好和 von Frey 试验评估冷觉和机械性超敏反应。检查外周神经和背根神经节的形态、脊髓 c-Fos 的表达、表皮内神经纤维密度以及背根神经节反应性氧/氮物种水平。同时或在奥沙利铂注射后给予 SS-31。
单次注射奥沙利铂引起前爪冷觉过敏，但后爪无此反应，数天内缓解（最大前爪抖动次数：28 ± 1.5 比 9.3 ± 1.6/150 s，均值 ± SEM，P < 0.001，每组 6 只）。奥沙利铂处理的小鼠比对照组更不喜欢 10°C 和 15°C 板。15°C 板刺激引起 C7-T1 节段背角浅层的 c-Fos 阳性细胞。每周给药引起后爪持续机械性痛觉过敏的逐渐发展（最小机械阈值：0.19 ± 0.08 比 0.93 ± 0.11 g，P < 0.001，每组 10 只）。显微镜检查未发现周围神经和背根神经节有明显的形态变化。同时给予 SS-31 可减轻反复奥沙利铂给药引起的冷觉和机械性超敏反应。表皮内神经纤维减少和背根神经节反应性氧/氮物种增加也得到减轻。在症状出现后急性给予 SS-31 仅能逆转冷觉过敏。
本奥沙利铂诱导周围神经病变模型模拟了患者的病情。SS-31 具有预防急性和慢性神经病变的潜力，但仅对急性神经病变有帮助。（麻醉学 2014；120：459-73）
