Martín-Ramírez Rita, González-Nicolás María Ángeles, Álvarez-Tosco Karen, Machín Félix, Ávila Julio, Morales Manuel, Lázaro Alberto, Martín-Vasallo Pablo
Laboratorio de Biología del Desarrollo, UD de Bioquímica y Biología Molecular, Universidad de La Laguna, 38206 San Cristóbal de La Laguna, Spain.
Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38071 San Cristóbal de La Laguna, Spain.
Cells. 2025 Aug 20;14(16):1294. doi: 10.3390/cells14161294.
Oxaliplatin-induced peripheral neurotoxicity (OIPN) represents a major challenge in cancer therapy, characterized by dorsal root ganglia (DRG) inflammation and disruption of neuro-glio-vascular unit function. In this study, we investigated the involvement of the scaffold protein IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) and dehydropeptidase-1 (DPEP1) in the DRG response to oxaliplatin (OxPt) and the modulatory effect of cilastatin. Behavioral assessment showed a robust nocifensive response to cold stimuli in OxPt-treated rats, attenuated by cilastatin co-treatment. Our confocal study revealed different cellular and subcellular expression patterns of IQGAP1 and DPEP1 in neurons, glia, and endothelial cells, where both signals overlap approximately one-third. OxPt enhanced cytosolic aggregation of IQGAP1 in neurons and upregulation of signal in glia, accompanied by co-expression of TNFα and IL-6, indicating involvement in the inflammatory process. DPEP1 showed altered subcellular distribution in OxPt-treated animals, suggesting a potential role in the inflammatory cascade. Notably, IQGAP1 expression was diminished in endothelial membranes under OxPt, while cilastatin preserved endothelial IQGAP1-CD31 colocalization, suggesting partial restoration of blood-nerve barrier integrity. These findings identify IQGAP1 and DPEP1 as key players in DRG inflammation and position cilastatin as a promising modulator of OIPN through neuro-glio-vascular stabilization.
奥沙利铂诱导的周围神经毒性（OIPN）是癌症治疗中的一项重大挑战，其特征为背根神经节（DRG）炎症以及神经-胶质-血管单元功能的破坏。在本研究中，我们调查了支架蛋白含IQ基序的GTP酶激活蛋白1（IQGAP1）和脱氢肽酶-1（DPEP1）在DRG对奥沙利铂（OxPt）反应中的作用以及西司他丁的调节作用。行为学评估显示，OxPt处理的大鼠对冷刺激有强烈的伤害性防御反应，而西司他丁联合处理可减轻这种反应。我们的共聚焦研究揭示了IQGAP1和DPEP1在神经元、神经胶质细胞和内皮细胞中的不同细胞及亚细胞表达模式，两者信号约有三分之一重叠。OxPt增强了神经元中IQGAP1的胞质聚集以及神经胶质细胞中信号的上调，并伴有TNFα和IL-6的共表达，表明其参与了炎症过程。DPEP1在OxPt处理的动物中显示出亚细胞分布改变，提示其在炎症级联反应中可能发挥作用。值得注意的是，在OxPt作用下，内皮细胞膜上的IQGAP1表达减少，而西司他丁保留了内皮IQGAP1与CD31的共定位，表明血-神经屏障完整性得到部分恢复。这些发现确定IQGAP1和DPEP1是DRG炎症的关键参与者，并将西司他丁定位为通过神经-胶质-血管稳定作用对OIPN有前景的调节剂。
