Evaluation of Liver X Receptor (LXR) Agonist Lansoprazole for the Treatment of Cardiac Cachexia

Abstract

BACKGROUND AND OBJECTIVE: Cachexia is a multiple organ metabolic disorder which is observed in many patients who are suffering from chronic illness such as heart failure, HIV, COPD, cancer, etc. In cardiac cachexia person usually suffers from unintentional weight loss and anorexia, along with loss of muscle strength and abnormal blood biomarkers. Cardiac cachexia can be defined as weight loss due to includes loss of skeletal muscle, cardiac muscle, and adipose tissue. Cardiac cachexia is caused by multiple factors associated with heart failure such as neurohormonal abnormality, elevated inflammatory cytokines, gastrointestinal malabsorption, catabolic anabolic imbalance, and anorexia. As of now, no particular treatment is available to alleviate cardiac cachexia. Liver X receptor (LXR) is a part of nuclear family receptor, which are ligand-activated transcription factors. LXRs are important metabolic pathway regulators. LXR play a significant role in regulating the metabolism of lipids and cholesterol. Moreover, activation of LXR also improves the carbohydrate metabolism which can improve the insulin resistance Apart from these, LXR activation also supress the inflammatory cytokines by inhibiting NF-κB signalling. Therefore, using LXR agonist might be helpful in treating the cachexia. Lansoprazole reported to act as a LXR agonist. Till now, lansoprazole has been reported to ameliorate glucose tolerance and supress inflammatory cytokines. However, no data is available of effect of lansoprazole in cardiac cachexia. Thus, the main objective of this investigation is to study the role of lansoprazole in cardiac cachexia. MATERIALS AND METHODS Balb/c of either sex, weighing 25–35 g at 6–8 weeks of age, was selected for the study and kept under regulated humidity (55–5%), temperature (22–2%), and 12–12–hour light–dark cycle conditions. Standard laboratory mice chow and UV-filtered water was provided. The The animals were injected intraperitoneally (i.p.) with (5 mg/kg) doxorubicin in 0.9% sodium chloride solution on every 5th, 10th and 15th day. Control animals was given equivalent amount of isotonic saline alone. Treatment with lansoprazole was started after the induction for 28 days. Lansoprazole (8 mg/kg) was dissolved in 0.5% methyl cellulose and given intraperitoneal in doxorubicin induced cardiac cachexia animals. Parameters evaluated were body mass markers, lipid metabolism markers, carbohydrate metabolism markers, cardiac atrophic markers, inflammatory marker, skeletal muscle wasting parameters, locomotor activity and histological analysis. RESULTS Body mass markers: After the induction of cardiac cachexia by doxorubicin, a significant decrease in the body weight, food intake, carcass weight and delta lean mass was observed in cardiac cachexia control group as compared to normal control animals. Treatment with lansoprazole increase the body weight, food intake, carcass weight and delta lean mass. Lipid metabolism markers: In cardiac cachexia control group, there was significant increase in the total cholesterol, triglyceride, LDL and VLDL levels as compared to normal control animals. Treatment with lansoprazole decrease the total cholesterol, triglyceride, LDL and VLDL levels. Additionally, the HDL level was increased in the cardiac cachexia control group as compared to normal control animals and lansoprazole treatment decrease the level of HDL. Carbohydrate metabolism: A significant increase in the blood glucose level was found in the cardiac cachexia control group as compared to normal control group. Treatment with lansoprazole significantly decrease the level of blood glucose. Cardiac complication marker: In cardiac cachexia control group, CK-MB level was significantly increased as compared to normal control animals. After the treatment with lansoprazole, a noteworthy decrease in the CK-MB level was observed in comparison to disease control group. Cardiac atrophic parameters: The weight of heart and heart weight to body weight ratio (HW/BW) was significantly increase in cardiac cachexia control group as compared to normal control animals. Treatment with lansoprazole substantially decrease the weight of heart and HW/BE ratio compared to disease control group. The ratio of left ventricular weight to heart weight (LV/HW) was decrease in cardiac cachexia control group but not significantly as compared to normal control animals. Treatment with lansoprazole increase the LV/HW ratio but not significantly as compared to disease control group. Inflammatory Markers: In cardiac cachexia control group, a significant increase in the level of IL-6 and TNF-α was observed as compared to normal control animals. Treatment with such as tibialis anterior (TA), extensor digitorium longus (EDL), gastrocnemius, soleus and quadriceps muscle was significantly decrease as compared to normal control animals. Treatment with lansoprazole significantly increase the weight of TA, EDL gastrocnemius, soleus and quadriceps muscle as compared to disease control group. Histological analysis: The histological analysis of the heart muscle and skeletal muscle in HE staining, showed increase in the disarrangement of muscle fibers along with apoptotic cell scar tissue was observed in cardiac cachexia control group. Treatment with lansoprazole showed proper arrangement of muscle fibre. Specific staining i.e. Masson trichrome and picro sirius red was used for collagen in the skeletal muscle. Decrease in the collagen was observed in the cardiac cachexia control group as compared to normal control animals. Treatment with lansoprazole showed increase amount of collagen as compared to disease control group. In HE staining of adipose tissue, adipocytes are seen by small lipid droplets cardiac cachexia control group. Treatment with lansoprazole showed larger lipid droplets with peripherally located nucleus. CONCLUSION Our data suggest that LXR agonist lansoprazole produces beneficial effect on cardiac cachexia by reducing the level of glucose, inflammatory cytokines, lipid levels and enhance the effects on cardiac muscle wasting, skeletal muscle wasting and fat tissue.