title: Protective role of S-nitrosoglutathione (GSNO) against cognitive impairment in rat model of chronic cerebral hypoperfusion.
abstract: Chronic cerebral hypoperfusion (CCH), featuring in most of the Alzheimer's disease spectrum, plays a detrimental role in brain amyloid-β (Aβ) homeostasis, cerebrovascular morbidity, and cognitive decline; therefore, early management of cerebrovascular pathology is considered to be important for intervention in the impending cognitive decline. S-nitrosoglutathione (GSNO) is an endogenous nitric oxide carrier modulating endothelial function, inflammation, and neurotransmission. Therefore, the effect of GSNO treatment on CCH-associated neurocognitive pathologies was determined in vivo by using rats with permanent bilateral common carotid artery occlusion (BCCAO), a rat model of chronic cerebral hypoperfusion. We observed that rats subjected to permanent BCCAO showed a significant decrease in learning/memory performance and increases in brain levels of Aβ and vascular inflammatory markers. GSNO treatment (50 μg/kg/day for 2 months) significantly improved learning and memory performance of BCCAO rats and reduced the Aβ levels and ICAM-1/VCAM-1 expression in the brain. Further, in in vitro cell culture studies, GSNO treatment also decreased the cytokine-induced proinflammatory responses, such as activations of NFκB and STAT3 and expression of ICAM-1 and VCAM-1 in endothelial cells. In addition, GSNO treatment increased the endothelial and microglial Aβ uptake. Additionally, GSNO treatment inhibited the β-secretase activity in primary rat neuron cell culture, thus reducing secretion of Aβ, suggesting GSNO mediated mechanisms in anti-inflammatory and anti-amyloidogenic activities. Taken together, these data document that systemic GSNO treatment is beneficial for improvement of cognitive decline under the conditions of chronic cerebral hypoperfusion and suggests a potential therapeutic use of GSNO for cerebral hypoperfusion associated mild cognitive impairment in Alzheimer's disease.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29245, USA.
authors.forename: Je-Seong
authors.initials: JS
authors.lastname: Won
authors.forename: Jinsu
authors.initials: J
authors.lastname: Kim
authors.forename: Balasubramaniam
authors.initials: B
authors.lastname: Annamalai
authors.forename: Anandakumar
authors.initials: A
authors.lastname: Shunmugavel
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D002908:Chronic Disease; D003072:Cognition Disorders / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione / Q000008:administration & dosage* / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D026422:S-Nitrosoglutathione