Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR.

Cisplatin is an effective and widely used first-line chemotherapeutic drug for treating cancers. However, many patients sustain cisplatin-induced peripheral neuropathy (CIPN), often leading to a reduction in drug dosages or complete cessation of treatment altogether. Therefore, it is important to understand cisplatin mechanisms in peripheral nerve tissue mediating its toxicity and identify signaling pathways for potential intervention. Rho GTPase activation is increased following trauma in several models of neuronal injury. Thus, we investigated whether components of the Rho signaling pathway represent important neuroprotective targets with the potential to ameliorate CIPN and thereby optimize current chemotherapy treatment regimens. We have developed a novel CIPN model in the mouse. Using this model and primary neuronal culture, we determined whether LM11A-31, a small-molecule, orally bioavailable ligand of the p75 neurotrophin receptor (p75NTR), can modulate Rho GTPase signaling and reduce CIPN. Von Frey filament analysis of sural nerve function showed that LM11A-31 treatment prevented decreases in peripheral nerve sensation seen with cisplatin treatment. Morphometric analysis of harvested sural nerves revealed that cisplatin-induced abnormal nerve fiber morphology and the decreases in fiber area were alleviated with concurrent LM11A-31 treatment. Cisplatin treatment increased RhoA activity accompanied by the reduced tyrosine phosphorylation of SHP-2, which was reversed by LM11A-31. LM11A-31 also countered the effects of calpeptin, which activated RhoA by inhibiting SHP-2 tyrosine phosphatase. Therefore, suppression of RhoA signaling by LM11A-31 that blocks proNGF binding to p75NTR or activates SHP-2 tyrosine phosphatase downstream of NGF receptor enhances neuroprotection in experimental CIPN in mouse model.

顺铂是一种有效且广泛应用的治疗癌症的一线化疗药物。然而，许多患者会出现顺铂诱导的周围神经病变（CIPN），这常常导致药物剂量减少或完全停止治疗。因此，了解顺铂在周围神经组织中的毒性作用机制以及确定可能的干预信号通路非常重要。在几种神经元损伤模型中，创伤后Rho GTP酶的激活会增加。因此，我们研究了Rho信号通路的组成部分是否是重要的神经保护靶点，是否有可能改善CIPN，从而优化当前的化疗治疗方案。我们在小鼠中建立了一种新的CIPN模型。利用该模型和原代神经元培养，我们确定了LM11A - 31（一种小分子、可口服的p75神经营养因子受体（p75NTR）的配体）是否能够调节Rho GTP酶信号并减轻CIPN。对腓肠神经功能的冯弗雷丝分析表明，LM11A - 31治疗可防止顺铂治疗所导致的周围神经感觉下降。对获取的腓肠神经进行形态计量分析显示，顺铂诱导的异常神经纤维形态以及纤维面积的减少在同时使用LM11A - 31治疗时得到缓解。顺铂治疗增加了RhoA的活性，同时伴有SHP - 2的酪氨酸磷酸化降低，而LM11A - 31可逆转这种情况。LM11A - 31还可对抗钙蛋白酶抑制剂的作用，钙蛋白酶抑制剂通过抑制SHP - 2酪氨酸磷酸酶来激活RhoA。因此，LM11A - 31通过阻断proNGF与p75NTR的结合或激活NGF受体下游的SHP - 2酪氨酸磷酸酶来抑制RhoA信号，从而在小鼠模型的实验性CIPN中增强神经保护作用。