Protective Effects And Molecular Mechanism Of Maltol On Acute Liver And Kidney Injury In Mice

Red ginseng is the root of Panax ginseng C. A Meyer(Araliaceae) with functions of Dabu strength, tonifying qi and controlling blood effectiveness. There are more complex Maillard reactions in red ginseng than food processing which could affect not only colors and smells but new constituents with pharmacology activity as well. Maltol(3-hydroxy-2-methyl-4pyrone) is one of the Maillard reaction products of maltose and amino acid which exerts good antioxidant activity. Furthermore, as one unique ingredient of red ginseng, maltol can effectively protect nerve cells against oxidative damage caused by reactive oxygen species in order to maintain normal physiological functions of cells. Maltol can also inhibit diabetes-induced oxidative stress and irreversible kidney damage. In this study, maltol is isolated from red ginseng and analyzed. Meanwhile, we established three kinds of toxicological mouse model, and then explored protective effects and possible molecular mechanism.1. A mouse model of alcohol-induced acute liver injury is established by feeding alcohol. Randomly distribute male ICR mice to normal group, alcohol group, Silymarin group(50 mg/kg) and low-, middle-, high- dose groups of maltol(12.5, 25, 50 mg/kg). Gavage for 15 days continuously, after the last dose, in addition to the normal group, administer 4.8g/kg of disposable gavage impact high doses of 50% alcohol to the rest groups, observe the status of mice. The results showed that, compared with the alcohol group, three different dose groups of maltol reduced ALT, AST, ALP and TG levels in serum to varying degrees, simultaneously, improve the activities of CAT, SOD and GSH-Px, reduced the MDA content, TNF-α and IL-1β levels in liver, and ameliorate pathological damage of hepatic tissue effectively and obviously. It has been suggested that the hepatoprotective effect exhibited by maltol on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.2. The hepatoprotective of maltol is further explored in a mouse model of acetaminophen-induced acute liver injury. Male C57BL/6J mice are randomly distributed to normal group, APAP group, Maltol-alone group(100 mg/kg) and APAP+Maltol group(100 mg/kg). Gavage for 7 days continuously, after the last dose, mice are administered with a single injection of acetaminophen(300 mg/kg i.p.) to induce acute liver injury. Results showed that, compared with the APAP group, different dose of maltol groups reduced ALT, AST activities and TNF-α, IL-1β and IL-6 levels in serum and MDA in liver to varying degrees. Simultaneously, improve the level of GSH and Bcl-2, reduce the expression of hepatic Bax, COX-2, NF-κB and 4-HNE, and ameliorate liver necrocytosis and congestion swelling effectively. Accordingly, pretreatment of maltol exhibit hepatoprotective activity on acetaminophen-induced acute liver injury.3. Another aim of this study is to explore the potential nephroprotective effect of maltol in a mice model of cisplatin-induced nephrotoxicity. ICR mice were randomly divided into five groups and treated for ten continuous days. The first group was used as a normal control. The second group was administered with a single injection of cisplatin(25 mg/kg i.p.) to induce nephrotoxicity. The third and the fourth groups were administered by oral gavage with maltol at a dose of 50 and 100 mg/kg, respectively once daily for ten days(7 days before and 3 days after cisplatin injection). The fifth group was treated with maltol alone for ten days(100 mg/kg i.p.). Mice were anaesthetized with carbon dioxide at 72 h after cisplatin injection and blood and kidney samples were collected. Increased blood urea nitrogen(BUN) and creatinine(CRE) levels in cisplatin alone treated mice were decreased to normal range by pretreatment with maltol. It also decreased oxidative stress and lipid peroxidation with increased antioxidant enzymes such as glutathione(GSH), superoxide dismutase(SOD), catalase(CAT) and decreased malondialdehyde(MDA) in maltol pretreated mice. The inhibition of inflammatory response by maltol was achieved through the reduction of TNF-α, IL-1β, iNOS, NF-κB and COX-2 expression. Simultaneously, histological examination indicated that maltol ameliorated renal damage caused by cisplatin. Additionally, pretreatment of maltol effectively relieved the overexpression of Caspase 3 or apoptotic cells in cisplatin-intoxicated mice observed by immunohistochemistry and immunofluorescence, Hoechst staining and TUnel assay. Our findings indicate that maltol might be a valuable candidate for the prevention and therapy of nephrotoxicity in patients receiving cisplatin.Taken together, in the above three different types of acute toxicology experiments in mice, maltol effectively ameliorate acute liver and kidney injury induced by alcohol or drug by improving antioxidant defense system function and inhibiting lipid peroxidation, inflammation, apoptosis and necrosis. The production of maltol and other phenolic compounds in Maillard reaction make red ginseng better bioactivity than fresh ginseng. Several molecular mechanisms have been found to be involved in liver or kidney injury such as oxidative stress, inflammation and apoptosis. It’s worth noting that the dosage of maltol in this study was based on the previous pathological studies and preliminary experiments in mice. As a safe and effective food additive, maltol is inexpensive and convenent. Therefore, clinical practice of maltol from food industry has far reaching significance.