Antidepressant effect of saxagliptin in an experimental model of depression in rats: Role of incretin

Abstract

Abstract Depression is recognized to be a worldwide, devastating mental illness, giving rise to poor quality of life and huge economic wastage. It distinguishes by many symptoms; such as persistent depressed mood, loss of pleasure, reduced energy, low self-assuredness, alterations in appetite, and poor concentration. Chronic exposure to stressful life events has been found to be involved in the etiology of neuropsychiatric diseases; such as depression. For that reasons, rats were revealed to an experimental model of chronic unpredictable mild stress (CUMS) model for 14 days. Diverse mild and unpredictable stressors were administered for 14 days in random times with the oral administration of saxagliptin (SAXA) (0.5, 1 and 2 mg/kg) to the treated rat groups. Saxagliptin which is a member of dipeptidyl peptidase-4 (DPP-4) inhibitors class, has been identified to elevate glucagon-like peptide-1 (GLP-1) level. The emergence of pharmacological agents; such as DPP-4 inhibitors is considered as an important rival in modifying neurodegenerative diseases as Alzheimer’s and Parkinson’s diseases in the preclinical studies. Accordingly, in the present study, SAXA is utilized to investigate its potential neuroprotective and antidepressant effect in an experimental model of chronic unpredictable mild stress (CUMS) in rats. The effect of SAXA is mostly linked to GLP-1/PI3K/AKT signaling pathway which upon its activation reportedly enhanced cellular survival, reversed neuronal damage and oxidative stress. It also is recognized by its potent anti-oxidant, anti-inflammatory, anti-apoptotic, and neuro-protective activities. SAXA treatment showed a significant elevation in the ambulation frequency, rearing score, grooming time and frequency in open field test (OFT). Additionally, the administration of SAXA displayed a significant increase in struggling time as well as a significant decrease in the immobility time in forced swimming test (FST). Moreover, the sucrose intake in sucrose preference test (SPT) was significantly enhanced in SAXA group. Saxagliptin treatment reversed the CUMS-induced changes in the histopathological examination.