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Xanthine Oxidase Inhibitor, Febuxostat Is Effective against 5-Fluorouracil-Induced Parotid Salivary Gland Injury in
Walaa Yehia Abdelzaher1, Mohamed A Nassan2, Sabreen Mahmoud Ahmed3,4
1Department of Pharmacology, Faculty of Medicine, Minia University, Minia 61519, Egypt.
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.
Insights
Febuxostat (FEB) protects against 5-fluorouracil (5-FU) induced parotid gland damage by reducing inflammation and oxidative stress. FEB also impacts the TRPC1/CHOP pathway, offering a novel therapeutic approach.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- 5-fluorouracil (5-FU) is a chemotherapy agent known to cause salivary gland damage.
- Febuxostat (FEB), a xanthine oxidase inhibitor, possesses pleiotropic pharmacological effects.
- The protective role of FEB against 5-FU-induced parotid damage requires further investigation.
Purpose of the Study:
- To investigate the ameliorative effects of febuxostat (FEB) on 5-fluorouracil (5-FU)-induced parotid salivary gland damage in rats.
- To evaluate the impact of FEB on oxidative stress, inflammation, and specific signaling pathways in the parotid gland.
Main Methods:
- Wistar rats were divided into four groups: control, FEB, 5-FU, and FEB/5-FU.
- FEB was administered orally for 14 days, followed by 5-FU intraperitoneal injections.
- Parotid gland damage was assessed through histological examination and biochemical analysis of oxidative stress markers, antioxidant defenses, inflammatory cytokines, TRPC1, and CHOP.
Main Results:
- FEB pre-treatment significantly reduced 5-FU-induced increases in malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β).
- FEB administration increased levels of nitric oxide (NOx), reduced glutathione (GSH), and superoxide dismutase (SOD) in parotid tissues.
- FEB pre-treatment notably elevated TRPC1 expression and decreased CHOP expression in the parotid gland.
Conclusions:
- Febuxostat demonstrates significant protective effects against 5-FU-induced parotid salivary gland damage.
- These protective effects are attributed to FEB's potent anti-inflammatory and antioxidant properties.
- FEB's modulation of the TRPC1/CHOP signaling pathway contributes to its therapeutic benefits in mitigating chemotherapy-induced salivary gland toxicity.
