Ultrastructural changes of endothelial cell, pericyte and vascular basement membrane in cisplatin-induced neuropathy in rats: correlation with neuropathic changes after treatments

Abstract

Cisplatin is an antineoplastic agent used to treat cancers of several organs. Peripheral neuropathy is one of its major side effects leading to dose reduction or cessation. Underlying mechanisms of cisplatin-induced neuropathy are not fully understood. According to current evidence, vascular dysfunction may play a role. Curcumin is a polyphenol found in the root of Curcuma longa with the anti-oxidant property and neuroprotection. Curcumin has shown effectiveness against experimental cisplatin neuropathy. B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and maintaining nervous system functions. Increasing evidence suggests the efficacy of vitamin B1-6-12 for several neurological diseases. Therefore, the objective of this study was to examine the ultrastructural changes of blood-nerve barrier (BNB) in the peripheral nerve and dorsal root ganglion (DRG) of rats treated with cisplatin and in vitro effects on rat brain vascular pericytes. Furthermore, the effects of curcumin and B vitamins were examined. Cisplatin neuropathy was induced by intraperitoneal injection of cisplatin 2 mg/kg twice a week for 5 consecutive weeks. The cisplatin-treated rats had reduced body weight, decreased heat sensitivity and slow nerve conduction velocity, indicating neuropathy. In the co-treatment group, curcumin or B vitamins was also given by gavage during the cisplatin treatment. Curcumin 200 mg/kg/day or B1-6-12 (100:100:1) 100, 300 and 600 mg/kg/day was given once daily. Curcumin and all doses of B1-6-12 could significantly improve the severity of neuropathy. Transmission electron microscope (TEM) study of capillaries in the sciatic nerve and DRG found that the cisplatin group had significantly higher frequency of separation and wider separation distance between endothelial cells and pericytes than the control group. Moreover, cisplatin significantly reduced viability of cultured pericytes. Curcumin and B1-6-12, especially low (100 mg/kg/day) and medium doses (300 mg/kg/day), could alleviate the cisplatin-induced pericyte detachment. These two agents also significantly improved pericyte viability. Taken together, cisplatin causes pericyte cytotoxicity in vitro and pericyte detachment in vivo. Curcumin and B1-6-12 are effective against these abnormalities and thus potential therapeutic agents for cisplatin-induced neuropathy. More investigations are needed to elucidate the underlying mechanisms and clinical applications.