Products Cited in Publications Worldwide In Vivo and Computational Studies on Sitagliptin’s Neuroprotective Role in Type 2 Diabetes Mellitus: Implications for Alzheimer’s Disease

In Vivo and Computational Studies on Sitagliptin’s Neuroprotective Role in Type 2 Diabetes Mellitus: Implications for Alzheimer’s Disease

Mani, Vasudevan; Arfeen, Minhajul

DOI:

Abstract

Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder charac_x005f_x0002_terized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM). Methods: T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings. Results: SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues. Conclusions: These findings highlight SITG’s neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations.

Keywords

sitagliptin ; type 2 diabetes mellitus ; Alzheimer’s disease ; brain enzymes ; inflammation ; oxidative stress ; apoptosis ; molecular docking

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Sitagliptin phosphate monohydrate

A323507654671-77-999%

Sitagliptin phosphate monohydrate

22.0/1g

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Streptozotocin

A66762518883-66-498% ≥85% α-anomer basis

Streptozotocin

28.0/100mg

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Nicotinamide HCl

A167123325334-23-098%

Nicotinamide HCl

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