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Oxygen-Glucose Deprivation and Reoxygenation as an In Vitro Ischemia-Reperfusion Injury Model for Studying Blood-Brain Barrier Dysfunction
Published on: May 7, 2015
DPP-4 inhibitor saxagliptin ameliorates oxygen deprivation/reoxygenation-induced brain endothelial injury
Xudong Zeng1, Xiaohui Li1, Zhenbo Chen1
1Department of Neurosurgery, Luoyang Central Hospital Affiliated to Zhengzhou University Luoyang 471039, Henan Province, China.
Insights
Saxagliptin, a DPP-4 inhibitor, protects human brain vascular cells from injury caused by oxygen and glucose deprivation. This diabetes drug reduces cell death, oxidative stress, and inflammation, highlighting its vascular protective potential.
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Cardiovascular diseases, particularly stroke, are major complications for diabetes patients.
- Dipeptidyl peptidase-4 (DPP-4) inhibitors are anti-glycemic drugs, with some showing cardiovascular benefits.
- Brain vascular endothelial cells are crucial for brain health and susceptible to ischemic injury.
Purpose of the Study:
- To investigate the vascular protective effects of saxagliptin against oxygen and glucose deprivation/reoxygenation (OGD/R) injury in human brain vascular endothelial cells.
- To elucidate the molecular mechanisms underlying saxagliptin's protective actions.
Main Methods:
- Human brain vascular endothelial cells were subjected to OGD/R.
- Cell viability was assessed using MTT assay, and cytotoxicity was measured by LDH assay.
- Mitochondrial membrane potential (MMP), oxidative stress markers (4-HNE, NOX-4), inflammatory cytokines (TNF-α, IL-6, MCP-1), and adhesion molecules (VCAM-1, E-selectin) were analyzed.
- NF-κB pathway activation was evaluated by assessing nuclear p65 translocation and promoter activity.
Main Results:
- DPP-4 expression was detected in brain endothelial cells and upregulated by OGD/R.
- Saxagliptin treatment significantly improved cell viability and reduced cytotoxicity induced by OGD/R.
- Saxagliptin preserved MMP, decreased oxidative stress markers, and suppressed pro-inflammatory cytokine and adhesion molecule production.
- Saxagliptin inhibited OGD/R-induced NF-κB pathway activation.
Conclusions:
- Saxagliptin demonstrates significant cellular protective effects against OGD/R-induced brain endothelial injury.
- The drug mitigates injury by reducing cell death, oxidative stress, inflammation, and inhibiting the NF-κB pathway.
- These findings support the potential of DPP-4 inhibitors, like saxagliptin, as therapeutic agents for protecting brain vasculature in diabetes.
Abstract:
Cardiovascular diseases are the main cause of death and disability among diabetes patients. Atherosclerosis-associated stroke is one of the most severe complications in diabetes patients. DPP-4 inhibitors are a class of potent anti-glycemic agents used to treat diabetes. Recently, some DPP-4 inhibitors have been shown to have cardiovascular benefits. In this study, we reveal that saxagliptin, one of the most widely used DPP-4 inhibitors, exhibits vascular protective effects against oxygen and glucose depletion/reoxygenation (OGD/R) in human brain vascular endothelial cells. Our data show that DPP-4 is fairly expressed in brain endothelial cells and its expression is induced by OGD/R. The results of MTT assay show that inhibition of DPP-4 by saxagliptin ameliorates OGD/R-induced reduced cell viability, and LDH assay demonstrated that saxagliptin reduces cellular toxicity. Furthermore, we show that saxagliptin mitigates OGD/R-induced collapse of mitochondrial membrane potential (MMP). Saxagliptin also reduces oxidative stress-induced release of 4-HNE and the NAPDH oxidase catalytic subunit NOX-4. At the molecular level, saxagliptin suppresses OGD/R-induced expression of pro-inflammatory cytokines and production of vascular adhesion molecules including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, monocyte chemoattractant protein 1 (MCP-1), vascular cellular adhesion molecule 1 (VCAM-1), and E-selectin. Mechanistically, saxagliptin inhibits activation of the NF-κB pathway by OGD/R via its inhibitory effect on nuclear p65 and NF-κB promoter activity. Collectively, our study explicitly demonstrates the cellular protective effect of saxagliptin against OGD/R-induced brain endothelial injury. Our findings extend our recognition of the protective roles of DPP-4 inhibitors in brain vascular cells.
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