Cilastatin Modulates DPEP1- and IQGAP1-Associated Neuro-Glio-Vascular Inflammation in Oxaliplatin-Induced Peripheral Neurotoxicity
Year: 2025
Type: article
Abstract: 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.
Source: Cells
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,258
Awards: G1143390064, G1741170060, G2089018331, G2469686904, G2723561721, G2786256631, G2805740431, G291867186, G2960503643, G3381082104, G3629930966, G3708376037, G3739173541, G3863087849, G3970548895, G4085937745, G4195478454, G4201474701, G4471127485, G449320669, G4793792581, G5091836597, G5330640778, G5432011802, G6028867552, G6083266616, G6176637409, G6495251246, G6563382155, G6765813396, G6834752959, G6847761142, G6986364084, G7097144329, G7673932087, G7754358699, G7916187811, G8105251917, G8253758006, G8275837493, G8325155251, G8768286833, G881633056, G968705665
OpenAlex ID: W4413353095