The protection conferred against ischemia-reperfusion injury in the diabetic brain by N-acetylcysteine is associated with decreased dicarbonyl stress

• Published in: Free radical biology & medicine 2016-07, Vol.96, p.89-98
• Main Authors: Wang, Bin, Aw, Tak Yee, Stokes, Karen Y.
• Format: Article
• Language: English
• Subjects: Acetylcysteine - administration & dosage; Animals; Antioxidants - metabolism; Blood-Brain Barrier - drug effects; Brain; Brain - metabolism; Brain - pathology; Carbonyl stress; Cerebral Infarction - complications; Cerebral Infarction - drug therapy; Cerebral Infarction - metabolism; Cerebral Infarction - pathology; Diabetes; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Glucose - metabolism; Glutamate-cysteine ligase; Glutamate-Cysteine Ligase - genetics; Glutamate-Cysteine Ligase - metabolism; Glutathione; Glutathione - metabolism; Glyoxalase; Humans; Ischemia-reperfusion; Methylglyoxal; Mice; Oxidative Stress - drug effects; Pyruvaldehyde - metabolism; Reperfusion Injury - complications; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Stroke - complications; Stroke - drug therapy; Stroke - metabolism; Stroke - pathology
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2016.03.038

Diabetes, a risk factor for stroke, leads to elevated blood methylglyoxal (MG) levels. This is due to increased MG generation from the high glucose levels, and because diabetes impairs the glutathione (GSH)-glyoxalase system for MG elimination. MG glycates proteins and causes dicarbonyl stress. We investigated the contribution of MG and GSH to stroke outcome. Cerebral ischemia/reperfusion was performed in chemical-induced (streptozotocin) and genetic Akita mouse models of Type 1 diabetes. Brain infarction and functions of the GSH-dependent MG elimination pathway were determined. Diabetes increased post-ischemia-reperfusion cerebral infarct area in association with elevated MG and diminished GSH levels. Infarct size correlated with brain MG-to-GSH ratio. Expression of glutamate-cysteine ligase catalytic subunit (GCLc) was increased in diabetic brain. GCL activity was unchanged. MG-adducts were elevated in the diabetic brain and, using immunoprecipitation, we identified one of the bands as glycated occludin. This was accompanied by increased blood-brain barrier permeability. Total protein carbonyls were elevated, indicative of oxidative/carbonyl stress. N-acetylcysteine (NAC) corrected MG-to-GSH ratio, and reduced diabetic brain infarct area, occludin glycation and permeability. In addition, protein carbonyls were decreased by NAC. We showed that the diabetic brain exhibited a lower GSH-dependent potential for MG elimination, which contributed to increased protein glycation, and oxidative/carbonyl stress. The consequence of these changes was aggravated post-stroke brain injury. NAC administration protected against the exacerbated brain damage via restored GSH generation and normalization of the MG-to-GSH ratio and possibly by attenuating oxidative/carbonyl stress. This treatment could contribute to the successful management of stroke risk/outcome in diabetes. •Diabetes increases dicarbonyl stress and exacerbates stroke-induced brain injury.•The capacity for glutathione to eliminate methylglyoxal is decreased in diabetes.•Methylglyoxal:glutathione correlates with severity of brain injury in diabetic stroke.•Occludin is glycated and blood-brain barrier is disrupted in diabetic brain.•NAC, via GSH synthesis, reverses these changes and protects versus stroke in diabetes.