Restoring Brain Pathways Involved in Diabetes-Associated Neurocognitive Disorders: The Potential of Dipeptidyl Peptidase 4 Inhibitors as a Therapeutic Strategy

Abstract

Background: Diabetes, a widespread chronic metabolic disease, is projected to affect 783 million people globally by 2045. Recent studies emphasize the neuroprotective potential of dipeptidyl peptidase 4 (DPP4i) inhibitors, pointing toward a promising avenue for intervention in addressing cognitive challenges associated with diabetes. Due to limited data on the effect of DPP4i on brain pathways involvedin diabetes-related neurocognitive disorders, the decision was made to conduct this study to fill existing knowledge gaps on this topic.

Methods: The primary aim of our study was to evaluate the potential of DPP4 inhibitors (DPP4i) in preventing cognitive decline in mice with type 2 diabetes (T2D), placing special emphasis on gaining insight into the complex molecular mechanisms underlying this action.

Results: We examined drug efficacy in modulating neurotrophic factors, calcium levels, and the expression of key genes (HIF1α, APP, Arc) crucial for neural plasticity. Conducting cognitive assessments with the hole board and passive avoidance tests, we discerned a remarkable influence of shortterm gliptin usage on the limiting progress of cognitive dysfunction in diabetic mice. The administration of DPP4 inhibitors ledto heightened neurotrophin levels, increased HIF1α in the prefrontal cortex, and a significant elevation in Arc mRNA levels.

Conclusion: Our findings reveal that DPP4 inhibitors effectively limit the progression of diabetesrelated cognitive disorders. This breakthrough discovery not only opens new research avenues but also constitutes a potential starting point for creating innovative strategies for the treatment of central nervous system disorders focused on improving cognitive abilities.

Keywords: APP; Arc.; Dipeptidyl peptidase 4 inhibitors; HIF1α; diabetes; neurotrophins.

Fig. (1)

Effect of linagliptin, saxagliptin, and sitagliptin on long-term memory in hole board test performance in diabetic mice. (A) The hole-board apparatus, (B) Exploratory activity of mice after 14 days of treatment (the stages of test: training (TR) and testing (TS), (C) Memory Performance Index (%). Statistical analysis was performed using a repeated measure ANOVA (Fig. 1B) and a parametric one-way ANOVA, followed by Tukey's post hoc test (Fig. 1C), with a significance level of p < 0.05 and a sample size of n = 8. *p < 0.05, (*) vs. CTL group; ^#p < 0.05, ^##p < 0.01, (^#) vs. DM group.

Fig. (2)

Effect of linagliptin, saxagliptin, and sitagliptin on long-term memory in passive avoidance test performance in diabetic mice. (A) The passive avoidance apparatus, (B) Latency time (sec). Statistical analysis was performed using parametric one-way ANOVA, followed by Tukey's post hoc test, with a significance level of p < 0.05 and a sample size of n = 8. *p < 0.05 vs. CTL; ^#p < 0.05 vs. DM group.

Fig. (3)

The impact of DPP4i on the expression levels of protein markers and calcium in the prefrontal cortex of diabetic mice, a brain region closely associated with learning and memory processes. (A) BDNF protein level, (B) NT4 level, (C) Calcium level, (D) HIF1α level, (E) APP level. Statistical analysis was performed using parametric one-way ANOVA, followed by Tukey's post hoc test, with a significance level of *p < 0.05 and a sample size of n=8. **p < 0.01, ***p < 0.001 vs. CTL; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 vs. DM group.

Fig. (4)

Effect of 14-day administration of linagliptin, saxagliptin, and sitagliptin on mean relative quantification of mRNA Arc gene expression (in correspondence to Hprt and Tbp gene expression) in the hippocampus and prefrontal cortex of diabetic mice. (A) Expression levels of Arc mRNA in the hippocampus (HIP); (B) Expression levels of Arc mRNA in the prefrontal cortex (PC). Statistical analysis was performed using parametric one-way ANOVA, followed by Tukey's post hoc test, with a significance level of p < 0.05 and a sample size of n=8. ***p < 0.001 vs. CTL; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 vs. DM group.