Impact of Lesinurad and allopurinol on experimental Hyperuricemia in mice: biochemical, molecular and Immunohistochemical study

Youssef Saeed Alghamdi,Mohamed Abdo Nassan,Mohamed Mohamed Soliman

doi:10.1186/s40360-020-0386-7

Youssef Saeed Alghamdi, Mohamed Abdo Nassan + Show 1 more

Open Access

https://doi.org/10.1186/s40360-020-0386-7

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Abstract

BackgroundHyperuricemia is an abnormal increase in uric acid levels in the blood. It is the cause of gout that manifested by inflammatory arthritis and painful disable. Therefore, current study evaluated the potential ameliorative impact of Lesinurad and Allopurinol on the kidneys of hyperuricemic mice at the biochemical, molecular and cellular levels.MethodsLesinurad and allopurinol alone or in combination were orally administered to hyperuricemic and control mice for seven consecutive days. Levels of uric acid and blood urea nitrogen, along with antioxidants and inflammatory cytokines (IL-1β and TNF-α) were measured in the serum. The mRNA expression of mouse urate anion transporter-1, glucose transporter 9, organic anion transporters, in renal tissues were examined using quantitative real time PCR. Simultaneously, the immunoreactivity of transforming growth factor-beta 1 was examined immunohistochemically.ResultsLesinurad and allopurinol administration resulted in significant decrease in serum levels of uric acid, blood urea nitrogen, xanthine oxidase activity, catalase, glutathione peroxidase and inflammatory cytokines (IL-1β and TNF-α) reported in hyperuricemic mice. Both partially reversed oxonate-induced alterations in renal mURAT-1, mGLUT-9, mOAT-1 and mOAT-3 expressions, as well as alterations in the immunoreactivity of TGF- β1, resulting in the increase of renal uric acid secretion and excretion. The combined administration of lesinurad and ALP restored all altered parameters in a synergistic manner, improving renal function in the hyperuricemic mouse model employed.ConclusionThis study confirmed synergistic ameliorative hypouricemic impact of both lesinurad and allopurinol in the treatment of hyperuricemia in mice at the biochemical, molecular and cellular levels.

Highlights

Hyperuricemia is an abnormal increase in uric acid levels in the blood
The impact of Lesinurad and ALP on liver and kidney biomarkers in hyperuricemic mice Hyperuricemic group showed an increase in serum levels of glutamate pyruvate transaminase (GPT), glutamate oxalate transaminase (GOT), uric acid and blood urea nitrogen (BUN)
The impact of Lesinurad and ALP on serum and hepatic Xanthine oxidase (XOD) activity As shown in Fig. 2, there was an increase of XOD activities in serum and liver of hyperuricemic mice., This increase in XOD activity were significantly normalized to control levels in ALP and ZUR administered hyperuricemic mice

Summary

Introduction

Hyperuricemia is an abnormal increase in uric acid levels in the blood. Uric acid (UA) is the end product of an exogenous and endogenous pool of purines metabolism. The endogenous pool depends on the production of uric acid from the liver, intestines and other tissues [1]. Gout is associated with precipitation of monosodium urate (MSU) crystals in joints and soft tissues [10, 11]. Other anti-inflammatory non-steroidal drugs known to inhibit cyclooxygenase activity (i.e. cortisol, indomethacin and glucocorticoids) are beneficial for the treatment of gout [13]. These medications have severe side effects and interactions capable of harming human health [14]

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