title: S-nitrosoglutathione prevents blood-brain barrier disruption associated with increased matrix metalloproteinase-9 activity in experimental diabetes.
abstract: Hyperglycemia is known to induce microvascular complications, thereby altering blood-brain barrier (BBB) permeability. This study investigated the role of matrix metalloproteinases (MMPs) and their endogenous inhibitors in increased BBB permeability and evaluated the protective effect of S-nitrosoglutathione (GSNO) in diabetes. Diabetes was induced in mice by intraperitoneal injection of streptozotocin (40 mg/kg body weight) for 5 days and GSNO was administered orally (100 μg/kg body weight) daily for 8 weeks after the induction of diabetes. A significant decline in cognitive functions was observed in diabetic mice assessed by Morris water maze test. Increased permeability to different molecular size tracers accompanied by edema and ion imbalance was observed in cortex and hippocampus of diabetic mice. Furthermore, activity of both pro and active MMP-9 was found to be significantly elevated in diabetic animals. Increased in situ gelatinase activity was observed in tissue sections and isolated microvessels from diabetic mice brain. The increase in activity of MMP-9 was attributed to increased mRNA and protein expression in diabetic mice. In addition, a significant decrease in mRNA and protein expression of tissue inhibitor of matrix metalloproteinase-1 was also observed in diabetic animals. However, GSNO supplementation to diabetic animals was able to abridge MMP-9 activation as well as tissue inhibitor of matrix metalloproteinase-1 levels, restoring BBB integrity and also improving learning and memory. Our findings clearly suggest that GSNO could prevent hyperglycemia-induced disruption of BBB by suppressing MMP-9 activity.
authors.affiliation: Department of Biochemistry, Basic Medical Science Building, Panjab University, Chandigarh, India.
authors.forename: Aanchal
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Department of Biochemistry, Basic Medical Science Building, Panjab University, Chandigarh, India.
authors.forename: Alka
authors.initials: A
authors.lastname: Khera
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Basic Medical Science Building, Panjab University, Chandigarh, India.
authors.forename: Rajat
authors.initials: R
authors.lastname: Sandhir
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018782:Maze Learning; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D026422:S-Nitrosoglutathione / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D019715:Tissue Inhibitor of Metalloproteinase-1; D026422:S-Nitrosoglutathione; D020780:Matrix Metalloproteinase 9
keywords: GSNO; blood-brain barrier; cognition; diabetes; matrix metalloproteinases; tissue inhibitor of matrix metalloproteinases