Pericyte loss and detachment in experimental cisplatin-induced neuropathy / Pérdida y desprendimiento de pericitos en la neuropatía experimental inducida por cisplatino

Cisplatin is an antineoplastic agent with neuropathy as one of its major side effect. However, effective treatment is lacking. Increasing evidence suggests that cisplatin might damage nerve capillaries leading to impaired functions of blood-nerve barrier (BNB) and neuropathy. This study was aimed to examine the effects of cisplatin on pericytes. Rats were either treated with intraperitoneal injection of cisplatin 2 mg/kg twice a week for five continuous weeks. Cisplatin-treated rats showed reduced body weight, thermal hypoalgesia and slow sciatic motor nerve conduction velocity, indicating neuropathy. The density of pericytes in the distal sciatic nerves determined by immunohistochemistry to desmin was significantly reduced in the cisplatin compared with that of the control groups. Electron microscopic analysis demonstrated the detachment of pericytes from endothelial cells including the disruption of shared basement membrane in the sciatic nerves from cisplatin-treated rats. These data indicate the pericyte loss and detachment caused by cisplatin. Future studies of the BNB components and functions after cisplatin treatment are needed and will be essential for the development of effective treatments against cisplatin-induced neuropathy.

El cisplatino es un agente antineoplásico y presenta como uno de sus principales efectos secundarios, la neuropatía. Sin embargo, falta un tratamiento eficaz. La creciente evidencia sugiere que el cisplatino podría dañar los capilares nerviosos, lo que puede provocar una alteración de las funciones de la barrera hematoencefálica (BHE) y neuropatía. Este estudio tuvo como objetivo examinar los efectos del cisplatino en los pericitos. Las ratas se trataron con inyección intraperitoneal de cisplatino (2 mg/kg) dos veces por semana durante 5 semanas seguidas. Las ratas tratadas con cisplatino mostraron una reducción del peso corporal, hipoalgesia térmica y una velocidad de conducción del nervio ciático lenta, lo que indicaría neuropatía. La densidad de los pericitos en los nervios ciáticos distales determinada por inmunohistoquímica para desmina se redujo significativamente en el grupo cisplatino en comparación con la de los grupos controles. El análisis al microscopio electrónico demostró el desprendimiento de pericitos de las células endoteliales, incluida la ruptura de la membrana basal compartida en los nervios ciáticos de ratas tratadas con cisplatino. Estos datos indican la pérdida de pericitos y el desprendimiento causado por el cisplatino. Se necesitan estudios futuros de los componentes y funciones del BHE después del tratamiento con cisplatino y serán esenciales para el desarrollo de tratamientos efectivos contra la neuropatía inducida por el cisplatino.

Methylglyoxal Induces Apoptosis Mediated by Reactive Oxygen Species in Bovine Retinal Pericytes

One of the histopathologic hallmarks of early diabetic retinopathy is the loss of pericytes. Evidences suggest that the pericyte loss in vivo is mediated by apoptosis. However, the underlying cause of pericyte apoptosis is not fully understood. This study investigated the influence of methylglyoxal (MGO), a reactive -dicarbonyl compound of glucose metabolism, on apoptotic cell death in bovine retinal pericytes. Analysis of internucleosomal DNA fragmentation by ELISA showed that MGO (200 to 800 micrometer) induced apoptosis in a concentration-dependent manner. Intracellular reactive oxygen species were generated earlier and the antioxidant, N-acetyl cysteine, inhibited the MGO-induced apoptosis. NF-kB activation and increased caspase- 3 activity were detected. Apoptosis was also inhibited by the caspase-3 inhibitor, Z-DEVD-fmk, or the NF- kB inhibitor, pyrrolidine dithiocarbamate. These data suggest that elevated MGO levels observed in diabetes may cause apoptosis in bovine retinal pericytes through an oxidative stress mechanism and suggests that the nuclear activation of NF-kB are involved in the apoptotic process.