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

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.

Diacerein modulates TLR4/ NF‐κB/IL‐1β and TRPC1/CHOP signalling pathways in gentamicin‐induced parotid toxicity in rats

“…19 The findings of this study revealed that GNT caused parotid toxicity through a variety of mechanisms. Damage to the salivary gland is caused by an imbalance between oxidative stress, inflammation, and apoptosis, 20 which are induced by GNT, as revealed in our results. Our study has obviously detected the ability of gentamycin to induce oxidative stress in rat parotid gland and plasma, as shown by a significant decrease in parotid SOD and serum TAC levels and a significant increase in parotid MDA, an indicator of lipid peroxidation that results in oxidative instability.…”

Atrophy and Inflammatory Changes in Salivary Glands Induced by Oxidative Stress after Exposure to Drugs and Other Chemical Substances: A Systematic Review

“…Out of 1756 articles, 26 articles regarding the effect of different substances on salivary glands were included in the analysis ( Figure 1 ). Their distribution was: 6 articles on the effect of chemotherapy drugs on salivary glands [ 5 , 12 , 15 , 16 , 18 , 19 ]; 4 articles on the effect of ethanol on salivary glands [ 6 , 7 , 9 , 20 ]; 9 articles on the effects of heavy metals on salivary glands [ 2 , 11 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]; 3 articles on the effect of fluoride on salivary gland [ 4 , 10 , 28 ]; 4 articles on the effect of other substances, such as atrazine [ 29 ], high protein diet [ 8 ], hyperoxia [ 30 ], and sodium nitrite [ 31 ]; All included studies were case-control studies. The two types of laboratory animals used were rats and mice.…”

“…Most of the studies have used tissular homogenate for biochemical analysis of oxidative and antioxidative markers, along with routine hematoxylin eosin (HE) and immunohistochemical analysis for histopathological and immunohistochemical diagnosis. While some studies evaluated changes in oxidative stress biomarkers in saliva, only a few studies have used animal models to additionally evaluate the histopathological changes after antioxidant therapy at the level of salivary glands [ 12 , 15 , 16 ].…”

“…6 articles on the effect of chemotherapy drugs on salivary glands [5,12,15,16,18,19]; • 4 articles on the effect of ethanol on salivary glands [6,7,9,20]; • 9 articles on the effects of heavy metals on salivary glands [2,11,[21][22][23][24][25][26][27]; • 3 articles on the effect of fluoride on salivary gland [4,10,28]; • 4 articles on the effect of other substances, such as atrazine [29], high protein diet [8], hyperoxia [30], and sodium nitrite [31];…”

Pregnancy and COVID-19: high or low risk of vertical transmission

“…In contrast, remdesivir is a prodrug that needs to be activated by host intracellular enzymes and converted to an active drug that inhibits viral RNA polymerase. It was originally developed to treat Marburg and Ebola virus infections before being repurposed to treat SARS-CoV-2 infections [ 80 – 82 ]. The most common adverse effects of remdesivir involve elevated liver enzymes, nausea, sweating, and hypotension, and remdesivir metabolism is affected by enzyme inducers or inhibitors [ 83 ].…”