Optimization of a cisplatin model of chemotherapy-induced peripheral neuropathy in mice: use of vitamin C and sodium bicarbonate pretreatments to reduce nephrotoxicity and improve animal health status.
Optimization of a cisplatin model of chemotherapy-induced peripheral neuropathy in mice: use of vitamin C and sodium bicarbonate pretreatments to reduce nephrotoxicity and improve animal health status.
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DOI：
10.1186/1744-8069-10-56
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发表时间：
2014-09-04
期刊：
影响因子：
3.3
通讯作者：
Hohmann AG
中科院分区：
文献类型：
--
作者：
Guindon J;Deng L;Fan B;Wager-Miller J;Hohmann AG
顺铂是一种铂衍生的化疗剂，产生毒性神经性疼痛和一般健康状况受损的副作用。这些副作用使动物神经病或镇痛干预的长期研究复杂化。我们最近证明，在顺铂之前用碳酸氢钠（4%NaHCO3）预处理（每周腹膜内3 mg/kg，长达5周）与改善大鼠的健康状况（即正常体重增加、体温、肌酸酐和酮水平以及肾重量比）相关（Neurosci Lett 544：41-46，2013）。为了减少顺铂治疗对小鼠的肾毒性作用，我们比较了碳酸氢钠（4%NaHCO3 s.c.），维生素C（25 mg/kg s.c.），白藜芦醇（25 mg/kg s.c.）和生理盐水（0.9%NaCl）预处理对顺铂诱导的动物健康状况、神经病理性疼痛和脊髓和肾脏中促炎细胞因子水平的变化的影响。接受生理盐水预处理的顺铂处理小鼠表现出酮、肌酐和肾重量比升高，代表肾毒性。维生素C和碳酸氢钠降低肌酐/酮水平和肾脏重量比，而白藜芦醇使肌酐水平和肾脏重量比正常化，与生理盐水预处理相似。与生理盐水预处理相比，所有预处理均与酮水平降低相关。顺铂诱导的神经病变（即机械性和冷异常性疼痛）在所有预处理组中发展相当，并且通过吗啡（6 mg/kg i. p.）或布洛芬（6 mg/kg i. p.）治疗RT-PCR结果显示，顺铂预处理组、生理盐水预处理组、NaHCO 3预处理组和白藜芦醇/顺铂预处理组大鼠腰髓中IL-1β mRNA水平均升高。然而，在所有顺铂治疗组中，肾脏中的IL-6和TNF-α升高。我们的研究还表明，在最后一次顺铂治疗后60天，体重、体温、肾功能和mRNA水平已恢复至基线，尽管神经性疼痛（机械性和寒冷性）仍在维持。采用顺铂的研究应包括NaHCO 3或维生素C预处理，以改善动物健康状况并降低肾毒性（降低肌酐和肾重量比），而不影响化疗诱导的神经病变或镇痛疗效的发生。
Cisplatin, a platinum-derived chemotherapeutic agent, produces antineoplastic effects coupled with toxic neuropathic pain and impaired general health status. These side-effects complicate long term studies of neuropathy or analgesic interventions in animals. We recently demonstrated that pretreatment with sodium bicarbonate (4% NaHCO3) prior to cisplatin (3 mg/kg i.p. weekly up to 5 weeks) was associated with improved health status (i.e. normal weight gain, body temperature, creatinine and ketone levels, and kidney weight ratio) in rats (Neurosci Lett 544:41-46, 2013). To reduce the nephrotoxic effects of cisplatin treatment in mice, we compared effects of sodium bicarbonate (4% NaHCO3 s.c.), vitamin C (25 mg/kg s.c.), resveratrol (25 mg/kg s.c.) and saline (0.9% NaCl) pretreatment on cisplatin-induced changes in animal health status, neuropathic pain and proinflammatory cytokine levels in spinal cord and kidney. Cisplatin-treated mice receiving saline pretreatment exhibited elevated ketone, creatinine and kidney weight ratios, representative of nephrotoxicity. Vitamin C and sodium bicarbonate lowered creatinine/ketone levels and kidney weight ratio whereas resveratrol normalized creatinine levels and kidney weight ratios similar to saline pretreatment. All pretreatments were associated with decreased ketone levels compared to saline pretreatment. Cisplatin-induced neuropathy (i.e. mechanical and cold allodynia) developed equivalently in all pretreatment groups and was similarly reversed by either morphine (6 mg/kg i.p.) or ibuprofen (6 mg/kg i.p.) treatment. RT-PCR showed that mRNA levels for IL-1β were increased in lumbar spinal cord of cisplatin-treated groups pretreated with either saline, NaHCO3 or resveratrol/cisplatin-treated groups. However, IL-6 and TNF-alpha were elevated in the kidneys in all cisplatin-treated groups. Our studies also demonstrate that 60 days after the last cisplatin treatment, body weight, body temperature, kidney functions and mRNA levels have returned to baseline although the neuropathic pain (mechanical and cold) is maintained. Studies employing cisplatin should include NaHCO3 or vitamin C pretreatment to improve animal health status and reduce nephrotoxicity (lower creatinine and kidney weight ratio) without affecting the development of chemotherapy-induced neuropathy or analgesic efficacy.
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影响因子：
2.5
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