Xanthine Oxidase Inhibitor, Febuxostat Is Effective against 5-Fluorouracil-Induced Parotid Salivary Gland Injury in Rats Via Inhibition of Oxidative Stress, Inflammation and Targeting TRPC1/CHOP Signalling Pathway.

Walaa Yehia Abdelzaher,Hanaa Mohamed Khalaf,Sabreen Mahmoud Ahmed,Nermeen N Welson,Mohamed A Nassan,Gaber El-Saber Batiha

doi:10.3390/ph15020232

Walaa Yehia Abdelzaher, Hanaa Mohamed Khalaf + Show 4 more

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https://doi.org/10.3390/ph15020232

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Abstract

The current research aimed to examine the ameliorative role of febuxostat (FEB), a highly potent xanthine oxidase inhibitor, against 5-fluorouracil (5-FU)-induced parotid salivary gland damage in rats, as FEB is a pleiotropic drug that has multiple pharmacological effects. A total of 32 Wistar adult male rats were randomly arranged into four groups. Group 1: the control group; given only the vehicle for 14 days, then given a saline i.p. injection from the 10th to the 14th day. Group 2: the FEB group; rats received FEB (10 mg/kg) once daily po for 14 days before receiving a saline i.p. injection from the 10th to the 14th day. Group 3: the 5-FU group; from the 10th to the 14th day, rats received an intraperitoneal injection of 5-FU (35 mg/kg/day). Group 4: the FEB/5-FU group; rats were pre-treated with FEB po for 14 days before receiving 5-FU i.p injections for five consecutive days from the 10th to the 14th day. Parotid gland damage was detected histologically and biochemically by the evaluation of oxidative stress markers (malondialdehyde (MDA) and nitric oxide levels (NOx)), oxidant defences (reduced glutathione (GSH) and superoxide dismutase (SOD)), inflammatory markers (tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β)), and transient receptor potential canonical1 (TRCP1) and C/EBP homologous protein (CHOP). FEB pre-treatment reduced MDA, TNF-, and IL-1 while increasing SOD, GSH, and NOx. FEB also significantly increased TRPC1 and decreased CHOP in parotid gland tissue. In conclusion, FEB pre-treatment reduced 5-FU-induced parotid salivary gland damage not only through its powerful anti-inflammatory and antioxidant effects, but also through its effect on the TRPC1/CHOP signalling pathway.

Highlights

Chemotherapeutic drugs are needed to treat cancer patients all over the world [1].Regrettably, they have several harmful effects on both normal and malignant cells, which are injured through a variety of pathways associated with the stomatognathic system’s key structures and functional activities [2,3]
Concerning FEB’s pleiotropic effects, the current study investigated its protective action against 5-FU-induced parotid gland damage, with a focus on its effects on key mediators such as transient receptor potential canonical1 (TRPC1), C/EBP homologous protein (CHOP), tumour necrosis factor-alpha (TNF-α), and interleukin 1 (IL-1β)
Rats pre-treated with FEB in a dose of 10 mg/kg showed a significant increase in ∆BW, parotid weight, and parotid index in comparison to the 5-FU group

Summary

Introduction

Chemotherapeutic drugs are needed to treat cancer patients all over the world [1] They have several harmful effects on both normal and malignant cells, which are injured through a variety of pathways associated with the stomatognathic system’s key structures and functional activities [2,3]. One of these chemotherapeutic medicines is fluorouracil (5-FU), which is used to treat solid malignancies such as breast, GIT, ovarian, Pharmaceuticals 2022, 15, 232. 5-FU caused deleterious pathological changes in the salivary glands and tongue mucosa [4]

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