Alogliptin reversed hippocampal insulin resistance in an amyloid-beta fibrils induced animal model of Alzheimer's disease.

Abstract

The complications of Alzheimer's disease (AD) have made the development of its treatment a challenging task. Several studies have indicated the disruption of insulin receptor substrate-1 (IRS-1) signaling during the development and progression of AD. The role of a dipeptidyl peptidase-4 (DPP-4) inhibitor on hippocampal IRS-1 signaling has not been investigated before. In this study, we evaluated the efficacy of alogliptin (DPP-4 inhibitor) on hippocampal insulin resistance and associated AD complications. In the present study, amyloid-β (1-42) fibrils were produced and administered intrahippocampally for inducing AD in Wistar rats. After 7 days of surgery, rats were treated with 10 and 20 mg/kg of alogliptin for 28 days. Morris water maze (MWM) test was performed in the last week of our experimental study. Post 24 h of final treatment, rats were euthanized and hippocampi were separated for biochemical and histopathological investigations. In-silico analysis revealed that alogliptin has a good binding affinity with Aβ and beta-secretase-1 (BACE-1). Alogliptin significantly restored cognitive functions in Aβ (1-42) fibrils injected rats during the MWM test. Alogliptin also significantly attenuated insulin level, IRS-1pS307 expression, Aβ (1-42) level, GSK-3β activity, TNF-α level and oxidative stress in the hippocampus. The histopathological analysis supported alogliptin mediated neuroprotective and anti-amyloidogenic effect. Immunohistochemical analysis also revealed a reduction in IRS-1pS307 expression after alogliptin treatment. The in-silico, behavioral, biochemical and histopathological analysis supports the protective effect of alogliptin against hippocampal insulin resistance and AD.

• Authors: Syed Obaidur Rahman, Madhu Kaundal, Mohd Salman, Apeksha Shrivastava, Suhel Parvez, Bibhu Prasad Panda, Mymoona Akhter, Mohd Akhtar, Abul Kalam Najmi
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 889 Pg. 173522 (Dec 15 2020) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 32866503 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Dipeptidyl-Peptidase IV Inhibitors
• Peptide Fragments
• Piperidines
• amyloid beta-protein (1-42)
• Uracil
• alogliptin

Topics

• Alzheimer Disease (chemically induced, drug therapy, metabolism)
• Amyloid (metabolism, toxicity)
• Amyloid beta-Peptides (antagonists & inhibitors, metabolism, toxicity)
• Animals
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Hippocampus (drug effects, metabolism)
• Insulin Resistance (physiology)
• Male
• Maze Learning (drug effects, physiology)
• Peptide Fragments (antagonists & inhibitors, metabolism, toxicity)
• Piperidines (pharmacology, therapeutic use)
• Random Allocation
• Rats
• Rats, Wistar
• Uracil (analogs & derivatives, pharmacology, therapeutic use)