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

Abstract

Background/objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized 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: Alzheimer’s disease; apoptosis; brain enzymes; inflammation; molecular docking; oxidative stress; sitagliptin; type 2 diabetes mellitus.

Figure 1

The timeline of the drug treatment and the experiment schedule.

Figure 2

Effect of diabetes and sitagliptin on body weight in rats over a 30-day treatment period (n = 6). Data are presented as mean ± SEM. ** p < 0.01 and *** p < 0.001 vs. Day-1 in Control; ## p < 0.01 and ### p < 0.001 vs. Day 1 in SITG10; $ p < 0.05 vs. Day 1 in T2DM + SITG30.

Figure 3

Effect of sitagliptin on blood glucose levels in diabetes-induced rats (n = 6). Data are presented as mean ± SEM. ** p < 0.01 and *** p < 0.001 vs. Day 1 in T2DM + SITG10; ### p < 0.001 vs. Day 1 in T2DM + SITG30.

Figure 4

Effect of sitagliptin on plasma insulin levels in diabetes-induced rats (n = 6). Data are presented as mean ± SEM. *** p < 0.001 vs. Control; ### p < 0.001 vs. T2DM.

Figure 5

Effect of sitagliptin on enzyme activity in the brains of diabetes-induced rats (n = 6): (A) AChE, (B) BACE-1, (C) DPP-4, and (D) GSK-3β. Data are presented as mean ± SEM. *** p < 0.001 vs. Control; ## p < 0.01 and ### p < 0.001 vs. T2DM.

Figure 6

Effect of sitagliptin on inflammatory markers in the brains of diabetes-induced rats (n = 6): (A) COX-2, (B) PGE2, (C) TNF-α, and (D) NF-κB. Data are presented as mean ± SEM. * p < 0.05 and *** p < 0.001 vs. Control; # p < 0.05 and ## p < 0.01 vs. T2DM.

Figure 7

Effect of sitagliptin on oxidative and antioxidant markers in the brains of diabetes-induced rats (n = 6): (A) MDA, (B) GSH, and (C) Catalase. Data are presented as mean ± SEM. ** p < 0.01 and *** p < 0.001 vs. Control; # p < 0.05, ## p < 0.01 and ### p < 0.001 vs. T2DM; $$ p < 0.01 vs. T2DM + SITG10.

Figure 8

Effect of sitagliptin on apoptotic proteins in the brains of diabetes-induced rats (n = 6): (A) Bcl-2, (B) BAX, and (C) Caspace-3. Data are presented as mean ± SEM. * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. Control; # p < 0.05, ## p < 0.01, and ### p < 0.001 vs. T2DM.

Figure 9

Binding mode of SITG in the active site of AChE, COX-2, GSK-3β, BACE-1, and Caspace-3.