Oxaliplatin (OHP) Induced Peripheral Neurotoxicity (OIPN) is one of the dose-limiting toxicities of the drug and these adverse effects limit cancer therapy with L-OHP, used for colorectal cancer treatment. Acute neurotoxicity consists of symptoms that are the hallmarks of a transient axonal hyperexcitability; chronic neurotoxicity has a clinical picture compatible with a length-dependent sensory neuropathy. Acute OIPN pathogenesis has been linked to sodium voltage-operated channels (Na + VOC) dysfunction and it has been advocated as a possible predisposing factor to chronic neurotoxicity. We tested if topiramate (TPM), a well-known Na + VOC modulator, was able to modify acute as well as chronic OIPN. The project was divided into two parts. In Experiment 1 we tested by means of Nerve Excitability Testing (NET) a cohort of female Wistar rats to assess TPM effects after a single OHP administration (5 mg/kg, iv). In Experiment 2 we assessed TPM effects after chronic OHP treatment (5 mg/kg, 2qw4ws, iv) using NET, nerve conduction studies (NCS), behavioral tests and neuropathology (caudal nerve morphometry and morphology and Intraepidermal Nerve Fiber [IENF] density). In Experiment 1 TPM was able to prevent OHP effects on Na + VOC: OHP treatment induced a highly significant reduction of the sensory nerve's threshold, during the superexcitability period (p-value = 0.008), whereas TPM co-administration prevented this effect. In Experiment 2 we verified that TPM was able to prevent not only acute phenomena, but also to completely prevent chronic OIPN. This latter observation was supported by a multimodal approach: in fact, only OHP group showed altered findings compared to CTRL group at a neurophysiological (proximal caudal nerve sensory nerve action potential [SNAP] amplitude, p-value = 0.001; distal caudal nerve SNAP amplitude, p-value<0.001, distal caudal nerve sensory conduction velocity, p-value = 0.04), behavioral (mechanical threshold, p-value 0.003) and neuropathological levels (caudal nerve fibers density, p-value 0.001; IENF density, p-value <0.001). Our data show that TPM is a promising drug to prevent both acute and chronic OIPN. These findings have a high translational potential, since they were obtained using outcome measures that match clinical practice and TPM is already approved for clinical use being free from detrimental interaction with OHP anticancer properties.

中文翻译：

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托吡酯可预防奥沙利铂相关的轴突过度兴奋和奥沙利铂引起的周围神经毒性。

奥沙利铂（OHP）诱导的周围神经毒性（OIPN）是该药物的剂量限制性毒性之一，这些不良反应限制了L-OHP的癌症治疗，该疗法用于结直肠癌的治疗。急性神经毒性包括症状，这些症状是短暂性轴突过度兴奋的标志。慢性神经毒性的临床表现与长度依赖性感觉神经病相容。急性OIPN发病机制与钠电压操纵通道（Na + VOC）功能障碍有关，已被提倡为慢性神经毒性的可能诱因。我们测试了著名的Na + VOC调节剂托吡酯（TPM）是否能够修饰急性和慢性OIPN。该项目分为两个部分。在实验1中，我们通过神经兴奋性试验（NET）测试了一组雌性Wistar大鼠，以评估单次OHP给药（5 mg / kg，静脉内）后的TPM效应。在实验2中，我们使用NET，神经传导研究（NCS），行为测试和神经病理学（尾神经形态和形态以及表皮内神经纤维[IENF]密度）评估了慢性OHP治疗（5 mg / kg，2qw4ws，iv）后的TPM效果。在实验1中，TPM可以预防OHP对Na + VOC的影响：OHP治疗可在超兴奋期内显着降低感觉神经阈值（p值= 0.008），而TPM共同给药则可以防止这种影响。在实验2中，我们验证了TPM不仅可以预防急性现象，而且还可以完全预防慢性OIPN。后一种观察得到了多模式方法的支持：实际上，与CTRL组相比，只有OHP组在神经生理学（近端尾神经感觉神经动作电位[SNAP]振幅，p值= 0.001；远端尾神经SNAP振幅）方面显示改变的发现，p值<0.001，远端尾神经感觉传导速度，p值= 0.04），行为（机械阈值，p值0.003）和神经病理学水平（尾神经纤维密度，p值0.001； IENF密度，p-值<0.001）。我们的数据表明，TPM是预防急性和慢性OIPN的有前途的药物。这些发现具有很高的翻译潜力，因为它们是使用与临床实践相匹配的结果指标获得的，并且TPM已被批准用于临床，且不会与OHP抗癌特性产生有害的相互作用。