Pharmacological Evaluation of PPAR-α/γ Dual Agonist in Modulation of Depressive-Like Behaviour Comorbid with Glucose Intolerance

Abstract

Background: Etiology of depression in hyperglycemic condition like diabetes is still poorly understood and there is immense need for finding better therapeutic approaches against such co-morbid disorders. The peroxisome proliferator-activated receptors (PPAR-α and γ) are gaining consistent interest as promising targets for treating neuropsychiatric disorders and behavioral dysfunctions. Given the findings that gallic acid has potential to act on PPAR-α and γ, it becomes an interesting to be investigate it for antidepressant activity. The present study investigates antidepressant effect of gallic acid on unpredictable chronic mild stress (UCMS) induced depression in hyperglycemic rats. Materials and methods: Hyperglycemia was induced in rats using dexamethasone (2mg/kg i.p.) for 7 days followed by UCMS procedure for three weeks to produce experimental model of hyperglycemia associated depression. Animals were administered with gallic acid (100mg/kg p.o.)/fluoxetine (2mg/kg p.o.)/metformin (140mg/kg p.o.) for 21 days. Behavioral paradigms like sucrose preference test, forced swim test, locomotor activity, novelty suppressed feeding, novel object recognition was performed. Biochemical estimation including glucose levels, oxidative stress parameters and neurotransmitter assay were performed. Results: Gallic acid treatment showed significant antidepressant activity in behavioural parameters. Further, treatment with gallic acid also demonstrated better cognitive ability. Further, gallic acid has proved to improve the neurobehavioral parameters as compared to disease control which was comparable to fluoxetine treated group. Gallic acid treatment normalized the elevated blood glucose in disease control rats. The levels of altered anti-oxidant parameters were improved after treatment with gallic. The altered levels of neurotransmitter like serotonin and dopamine were also improved. Histopathological evaluation of brain demonstrated increased neural density and restoration of normal neural morphology. Conclusion: Taken together, the result suggests antioxidant/neuroprotective effect of gallic acid via its action on PPAR-α and PPAR-γ, thus, helping combat depression associated with hyperglycemia.