Neuroprotective Role of DPP-4 Inhibitor Linagliptin Against Neurodegeneration, Neuronal Insulin Resistance and Neuroinflammation Induced by Intracerebroventricular Streptozotocin in Rat Model of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) and donepezil (5 mg/kg) as a standard for 8 weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Aβ (1-42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD.

Keywords: Alzheimer’s disease; Insulin Receptor Substrate-1; Linagliptin; Neuronal insulin resistance; Streptozotocin.