Cisplatin-induced alterations in the blood-nerve barrier: effects of combination of vitamin B1, B6 and B12.

Abstract

Cisplatin is a chemotherapeutic agent against solid cancers. However, neuropathy is a major side effect and has no effective treatment so far. Emerging evidence suggests that cisplatin might damage nerve capillaries leading to impaired blood-nerve barrier (BNB). This study aimed to investigate the ultrastructural changes of the BNB in the sciatic nerves and dorsal root ganglia of rats with cisplatin neuropathy and the effects of B1-6-12. The results showed that cisplatin 2 mg/kg injected intraperitoneally twice a week for 5 consecutive weeks caused thermal hypoalgesia and structural abnormalities of nerves and ganglia. Co-treatment with oral B1-6-12 (100:100:1) 100, 300 and 600 mg/kg/day for 5 weeks reduced the sensory deficit and structural alterations. Electron microscopic analysis demonstrated the higher frequencies and wider distances of pericyte detachment in the capillaries of cisplatin than control groups. Vitamin B1, B6 and B12 especially the medium dose, reversed these abnormalities. Culture of endothelial cells and pericytes with cisplatin demonstrated reduced cell viability, increased caspase-3 activity, lower transendothelial electrical resistance and decreased expression of tight junction proteins, occludin and zonula occluden-2. Vitamin B1, B6 and B12 could correct these toxic effects of cisplatin. These data confirm that cisplatin causes pathological alterations in the components of BNB which correlate with the severity of neuropathy. Furthermore, B1-6-12 is effective against these abnormalities and deserves further investigations as potential treatment for cisplatin-induced neuropathy.