Linagliptin, a DPP-4 inhibitor, ameliorates Aβ (1−42) peptides induced neurodegeneration and brain insulin resistance (BIR) via insulin receptor substrate-1 (IRS-1) in rat model of Alzheimer's disease. (1st September 2021)

• Record Type: Journal Article
• Authors: Siddiqui, Nazia; Ali, Javed; Parvez, Suhel; Zameer, Saima; Najmi, Abul Kalam; Akhtar, Mohd
• Is Part Of: Neuropharmacology. Volume 195(2021)
• Publication Date: 2021-09-01
• Subjects: Alzheimer's disease -- Brain insulin resistance -- Insulin receptor Substrate-1 -- Glucagon-like peptide-1 -- Linagliptin -- Amyloid beta (1−42); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2021.108662
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Alzheimer's disease (AD) is the most devastating neurodegenerative disorder, accounting over 46 million cases of dementia globally. Evidence supports that Brain Insulin Resistance (BIR) due to serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1) has an association with AD. GLP-1 an incretin hormone, rapidly degraded by Dipeptidyl Peptidase-4 (DPP-4) has also confirmed its efficacious role in AD. Linagliptin, a DPP-4 inhibitor is hypothesized to increase GLP-1 level, which then crosses Blood Brain Barrier (BBB), decreases Amyloid-beta (Aβ) and insulin resistance in hippocampus. Thus, the present study was designed to evaluate Linagliptin in Aβ (1−42) peptides induced rat model of AD. Following 1 week of induction, rats were administered with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) orally for 8 weeks and donepezil (5 mg/kg) as a reference standard. At the end of scheduled treatment neurobehavioral parameters were assessed. After this, rats were sacrificed, hippocampus was isolated from the whole brain for histopathological analysis and biochemical parameters estimation. Linagliptin dose-dependently and significantly reversed motor and cognitive impairment, assessed through locomotor activity (LA) and Morris water maze (MWM) test respectively. Moreover, Linagliptin augmented GLP-1 level and attenuated soluble Aβ (1−42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level in hippocampus. H&E and Congo red staining also exhibited neuroprotective and anti-amylodogenic effect respectively. Our study findings implies the significant effect of Linagliptin in reversing the behavioural and biochemical deficits by altering Aβ (1−42) and BIR via IRS-1 confirming one of the mechanism underlying the pathophysiology of AD. Highlights: DPP-4 inhibitors increases GLP-1 level, ameliorates T2DM. GLP-1 crosses BBB, decreases APP, Aβ peptides and increases insulin secretion. BIR or T3DM due to serine phosphorylation of IRS-1 at 307 through over activation of JNK. Microglial activation due to Aβ plaques releases pro-inflammatory cytokines results in BIR.