Vinpocetine Attenuates 5-Fluorouracil-Induced Renal Intoxication by Regulating Nrf2/ARE, NF-κB/TLR4, and NLRP3/ASC/Caspase-1 Signals in Rats

Abstract

Background: One of the most commonly used anti-cancer medications for various tumors is 5-fluorouracil (5-FU). However due to the accompanying nephrotoxicity, its clinical use is restricted.  Vinpocetine (VNP) is a derivative of vincamine alkaloid used to treat cognitive disorders and cerebrovascular diseases. 
Methods: In this study, 40 adult male Wistar rats were randomized into five groups, untreated animals (control), treated with VNP (20mg/kg), 5-FU (30mg/kg), 5-FU+VNP (10mg/kg), and 5-FU+VNP (20mg/kg). The results of all groups were compared to 5-FU rats. 
Results: VNP improved renal function by reducing serum urea, creatinine, and NGAL levels while it increased the serum level of albumin. VNP restored the oxidant-antioxidant balance of renal tissues mediated by increasing Nrf2/HO-1 expression. VNP suppressed the inflammation by decreasing MPO and NO2 and reducing IL-1β, TNF-α, and IL-6 levels mediated by suppressing TLR4 and NF-κB expression. Moreover, VNP downregulates NLRP3, ASC, and cleaved caspase 1. Histological analysis of kidney tissues validated our findings. Of note, VNP's Reno protective effects were dose-dependent. 
Conclusion: Our data suggest that co-treatment of VNP with 5-FU is a promising agent for mitigating 5-FU-induced nephrotoxicity by NF-κB/TLR4, Nrf2/ARE, and NLRP3/ASC/Caspase-1 signals.

Keywords

FU-induced nephrotoxicity, Vinpocetine, 5-Flurouracil, NF-κB/TLR4, Nrf2/ARE and NLRP3/ASC/Caspase-1.

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