Dehydropeptidase-1 in dorsal root ganglia and its relationship with scaffold proteins IQGAP1 and FKBP51 in oxaliplatin-induced neurotoxicity
- Autores: Karen Ilenia Álvarez Tosco
- Directores de la Tesis: Pablo Martín Vasallo (dir. tes.), Manuel José Morales González (codir. tes.)
- Lectura: En la Universidad de La Laguna ( España ) en 2025
- Idioma: español
- Tribunal Calificador de la Tesis: Diego Álvarez de la Rosa Rodríguez (presid.), María del Pilar Díaz Ruiz (secret.), Inmaculada Hernández González (voc.)
- Programa de doctorado: Programa de Doctorado en Ciencias de la Salud por la Universidad de La Laguna
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Oxaliplatin-induced peripheral neurotoxicity (OIPN) represents a major challenge that compromises efficacy of antineoplastic treatments. This syndrome is characterized by dorsal root ganglia (DRG) inflammation and disruption of neuroglio-vascular unit function. The objective of this study was to describe dehydropeptidase I (DPEP1) and two scaffold proteins, IQGAP1 and FKBP51, expression in rat DRG in healthy subjects, in early stages of oxaliplatin (OxPt) toxicity and after administration of cilastatin (CIL). To this end, we produced and characterized anti-DPEP1 polyclonal antibodies and used them to define the expression, and cellular and subcellular localization of DPEP1 by immunohistochemical confocal microscopy studies. Same studies were conducted with commercially available antibodies for IQGAP1 and FKBP51.
Behavioural assessment of animals showed a robust nocifensive response to cold stimuli in OxPt treated rats, attenuated by CIL co-treatment. Our confocal study revealed different cellular and subcellular expression patterns of DPEP1, IQGAP1 and FKBP51 in neurons, glia, and endothelial cells, including signals overlap. DPEP1 showed altered subcellular distribution in OxPt-treated animals, suggesting a potential role in the inflammatory cascade. OxPt enhanced cytosolic aggregation of IQGAP1 in neurons and upregulation of signal in glia, accompanied by co-expression of TNF and IL-6, indicating involvement in the inflammatory process. FKBP51 results showed an increased expression of this immunophilin under stress conditions in glial cells and absence in nuclei of neurons. CIL remarkably attenuated the OxPt-induced upregulation of TNF and IL-6, restoring their expression to near-control levels. This effect was not proportional to regulation of DPEP1 since CIL alone did not modify distribution or expression of this protein. CIL appeared to preserve physiological patterns of IQGAP1 localization and mitigate changes in FKBP51 after OxPt treatment.
These findings identify DPEP1, IQGAP1 and FKBP51 as key players in DRG inflammation and position CIL as a promising modulator of OIPN through neuro-glio-vascular stabilization.
