Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1-5 In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2 We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.

中文翻译：

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1-磷酸鞘氨醇受体2的激活减弱了化疗引起的神经病。

铂类疗法可用于治疗多种形式的癌症，但通常会导致周围神经病变。当前，可用于减轻化学疗法诱导的神经病的唯一选择是限制或终止该治疗。1-磷酸鞘氨醇（S1P）是一种基于脂质的信号分子，通过与它的五个同源受体相互作用而参与神经炎症过程：S1P1-5在这项研究中，结合了人类研究对象的药物药效学分析，啮齿动物的疾病建模，和基于细胞的分析，我们检查了S1P信号传导是否可能代表化学疗法诱发的神经病的潜在靶标。为此，我们首先研究了铂类药物对人类癌症患者血浆S1P水平的影响。我们的分析表明，在这些患者中，奥沙利铂治疗可特异性增加一种S1P种类，即d16：1 S1P。尽管d16：1 S1P是S1P2激动剂，但其效力比最丰富的S1P物种（d18：1 S1P）低。因此，随着d16：1 S1P浓度的增加，可能会过度地激活促炎性S1P1信号传导，使平衡从S1P2移开。我们进一步表明，选择性S1P2激动剂CYM-5478可以降低顺铂诱导的神经病大鼠模型的异常性疼痛。并可能通过激活包括ATF3和HO-1在内的应激反应蛋白来减轻背根神经节的相关炎症过程。累计