title: The protection conferred against ischemia-reperfusion injury in the diabetic brain by N-acetylcysteine is associated with decreased dicarbonyl stress.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA; Center for Cardiovascular Diseases and Sciences, LSU Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA; Department of Geriatrics, Union hospital, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA; Center for Cardiovascular Diseases and Sciences, LSU Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA.
authors.forename: Tak Yee
authors.initials: TY
authors.lastname: Aw
authors.affiliation: Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA; Center for Cardiovascular Diseases and Sciences, LSU Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA; Center for Molecular and Tumor Virology, LSU Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130, USA. Electronic address: kstoke@lsuhsc.edu.
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Stokes
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011765:Pyruvaldehyde / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D011765:Pyruvaldehyde; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D005947:Glucose; D000111:Acetylcysteine
keywords: Brain; Carbonyl stress; Diabetes; Glutamate-cysteine ligase; Glutathione; Glyoxalase; Ischemia-reperfusion; Methylglyoxal