Role of Antidiabetic Drugs In Modulation of Depressive-Like Behavior Comorbid With Glucose Intolerance: Activation of AMPK

Abstract

Aim and objective The diabetic patient double the risk of the depressive like behavior, the risk of depression increase up to 60 % in type 2 diabetes mellitus. The diabetes produce certain structural and biochemical changes in brain. Therefore objective of our study was to evaluate Antidiabetic drugs for treatment of diabetes associated depression. Materials and method In vitro evaluation: Five month old, mixed sexes of zebrafish were used for in vitro evaluation. Diabetes induced by 114 mMOL glucose in two litre water for 21 days. After induction of diabetes, UCMS model was performed for induction of depression. The treatment was carried out for 7 days and behavioural parameter were performed using T and Y maze.In- vivo evaluation: seven- to eight week-old male C57BL/6 mice weighing 25 ± 2 g were used for study. For induction of glucose intolersnce, 1% sucrose solution for 2 weeks. For induction of depression UCMS model was used which included different randomly stressor given to animals. After 2 weeks of induction, 4 weeks of treatment was given and behavioral parameters were performed followed by blood collection for determination of biochemical parameters. At the end animals were sacrificed and brain samples were isolated for determination of neurotransmitters assay for serotonin and dopamine, enzyme activity for AchE inhibition, MAO-A, MAO-B and aldose reductase and histopathological evaluation. Immunohistochemistry, gene (for AMPK, IL- 6, CNTF, MMP-9 and caspase 3), protein expression study and cell apoptosis by TUNEL assay was carried out. Results The result showed that empagliflozin reversed the effect of depressive behavior in zebrafish, as indicated by behavioral parameter using Y maze and T maze. The behavioral parameter FST and TST suggests that empagliflozin and saroglitazar ameliorates the depressive behavior as compared disease control group. The biochemical parameter has shown significant (p<0.05)effect of empagliflozin on depressive animals. Treatment has not significant increase dopamine level but its significantly increased serotonin level in both empagliflozin and saroglitazar treated groups. Enzyme activity and oxidative stress parameters have also shown beneficial effect of treatment on depressive animals. Histopathology and immunohistochemistry have showed that the less damage in neuron cells and astrocytes in treatment group. Gene expression studies of AMPK, IL-6, CNTF, MMP-9 and caspase 3 have suggested that the beneficial role of AMPK activator in depression induced animals. The cell apoptosis study showed that the number of dead cells have decrease in treatment group as compared to disease control group. Conclusion: From present study we can conclude that antidiabetic agents have beneficial effect in treatment of diabetes associated depression by activator of AMPK pathway.