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Targeting AGEs Signaling Ameliorates Central Nervous System Diabetic Complications in Rats
Mohamed Naguib Zakaria1, Hany M El-Bassossy2, Waleed Barakat3
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
Abstract:
Diabetes is a chronic endocrine disorder associated with several complications as hypertension, advanced brain aging, and cognitive decline. Accumulation of advanced glycation end products (AGEs) is an important mechanism that mediates diabetic complications. Upon binding to their receptor (RAGE), AGEs mediate oxidative stress and/or cause cross-linking with proteins in blood vessels and brain tissues. The current investigation was designed to investigate the effect of agents that decrease AGEs signaling, perindopril which increases soluble RAGE (sRAGE) and alagebrium which cleaves AGEs cross-links, compared to the standard antidiabetic drug, gliclazide, on the vascular and central nervous system (CNS) complications in STZ-induced (50 mg/kg, IP) diabetes in rats. Perindopril ameliorated the elevation in blood pressure seen in diabetic animals. In addition, both perindopril and alagebrium significantly inhibited memory decline (performance in the Y-maze), neuronal degeneration (Fluoro-Jade staining), AGEs accumulation in serum and brain, and brain oxidative stress (level of reduced glutathione and activities of catalase and malondialdehyde). These results suggest that blockade of AGEs signaling after diabetes induction in rats is effective in reducing diabetic CNS complications.
Insights
Agents blocking advanced glycation end product (AGE) signaling, like perindopril and alagebrium, effectively reduced vascular and central nervous system complications in diabetic rats. These findings highlight AGE signaling as a key target for treating diabetic complications.
Area of Science:
- Endocrinology
- Neuroscience
- Pharmacology
Background:
- Diabetes mellitus is a chronic endocrine disorder linked to severe complications, including hypertension, accelerated brain aging, and cognitive decline.
- Accumulation of advanced glycation end products (AGEs) is a primary mechanism driving these diabetic complications, mediated by receptor for AGEs (RAGE) signaling.
- AGEs binding to RAGE triggers oxidative stress and protein cross-linking in vascular and brain tissues, contributing to pathology.
Purpose of the Study:
- To investigate the efficacy of agents targeting AGE signaling pathways in mitigating vascular and central nervous system (CNS) complications of diabetes.
- To compare the effects of perindopril (increases soluble RAGE) and alagebrium (cleaves AGE cross-links) against gliclazide (standard antidiabetic drug) in a rat model of diabetes.
Main Methods:
- Streptozotocin (STZ)-induced diabetes in rats (50 mg/kg, IP).
- Administration of perindopril, alagebrium, or gliclazide.
- Assessment of blood pressure, cognitive function (Y-maze), neuronal degeneration (Fluoro-Jade staining), serum and brain AGEs levels, and markers of brain oxidative stress (reduced glutathione, catalase, malondialdehyde).
Main Results:
- Perindopril effectively normalized elevated blood pressure in diabetic rats.
- Both perindopril and alagebrium significantly attenuated memory deficits and neuronal degeneration.
- Treatment with perindopril and alagebrium markedly reduced AGE accumulation in serum and brain tissue.
- These agents also ameliorated markers of oxidative stress within the brain.
Conclusions:
- Blockade of AGEs signaling pathways demonstrates significant therapeutic potential in reducing both vascular and CNS complications associated with diabetes.
- Perindopril and alagebrium show promise as agents for managing diabetic complications by targeting AGEs.
- Targeting AGEs signaling represents a viable strategy for preventing or treating the multifaceted complications of diabetes.
