β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism
Nitric oxide (NO) toxicity is in part mediated by generation of peroxynitrite with concomitant production of superoxide under pathological brain conditions such as ischemia and Alzheimer’s disease. The pathophysiological relevance of endothelial nitric oxide synthase (eNOS) to brain embolism-induced...
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doaj-255ccccb5b0a4781bcc960d097bc05e02020-11-25T02:06:26ZengElsevierJournal of Pharmacological Sciences1347-86132009-01-011112101109β-Amyloid Accumulation in Neurovascular Units Following Brain EmbolismFeng Han0Kohji Fukunaga1Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, ChinaDepartment of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan; Corresponding author. fukunaga@mail.pharm.tohoku.ac.jpNitric oxide (NO) toxicity is in part mediated by generation of peroxynitrite with concomitant production of superoxide under pathological brain conditions such as ischemia and Alzheimer’s disease. The pathophysiological relevance of endothelial nitric oxide synthase (eNOS) to brain embolism-induced neurovascular injury has not been documented. We found that microsphere embolism (ME)–induced aberrant eNOS expression in vascular endothelial cells likely mediates blood-brain barrier (BBB) disruption via peroxynitrite formation and in turn causes brain edema. We also demonstrated that a mild ME model was useful for investigating the sequential events of neurovascular injury followed by β-amyloid accumulation and tau hyperphosphorylation. Indeed, immunoblotting of purified brain microvessels revealed that β-amyloid accumulation significantly increased one week after ME induction and remained elevated for twelve weeks in those animals. Moreover, we also confirmed that peroxynitrite formation and eNOS uncoupling–mediated superoxide generation in microvessels are inhibited by a novel calmodulin inhibitor. Thus, peroxynitrite formation via elevated eNOS is associated with endothelial cell injury with concomitant β-amyloid accumulation in microvessels of aged rats. In this review, we focus on the detrimental effects of eNOS expression following brain embolism and introduce an attractive model representing progressive Alzheimer’s disease pathology in brain. Keywords:: microsphere embolism, nitric oxide (NO), calmodulin, endothelial nitric oxide synthase (eNOS), peroxynitrite, β-amyloidhttp://www.sciencedirect.com/science/article/pii/S1347861319311089 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Feng Han Kohji Fukunaga |
spellingShingle |
Feng Han Kohji Fukunaga β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism Journal of Pharmacological Sciences |
author_facet |
Feng Han Kohji Fukunaga |
author_sort |
Feng Han |
title |
β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism |
title_short |
β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism |
title_full |
β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism |
title_fullStr |
β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism |
title_full_unstemmed |
β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism |
title_sort |
β-amyloid accumulation in neurovascular units following brain embolism |
publisher |
Elsevier |
series |
Journal of Pharmacological Sciences |
issn |
1347-8613 |
publishDate |
2009-01-01 |
description |
Nitric oxide (NO) toxicity is in part mediated by generation of peroxynitrite with concomitant production of superoxide under pathological brain conditions such as ischemia and Alzheimer’s disease. The pathophysiological relevance of endothelial nitric oxide synthase (eNOS) to brain embolism-induced neurovascular injury has not been documented. We found that microsphere embolism (ME)–induced aberrant eNOS expression in vascular endothelial cells likely mediates blood-brain barrier (BBB) disruption via peroxynitrite formation and in turn causes brain edema. We also demonstrated that a mild ME model was useful for investigating the sequential events of neurovascular injury followed by β-amyloid accumulation and tau hyperphosphorylation. Indeed, immunoblotting of purified brain microvessels revealed that β-amyloid accumulation significantly increased one week after ME induction and remained elevated for twelve weeks in those animals. Moreover, we also confirmed that peroxynitrite formation and eNOS uncoupling–mediated superoxide generation in microvessels are inhibited by a novel calmodulin inhibitor. Thus, peroxynitrite formation via elevated eNOS is associated with endothelial cell injury with concomitant β-amyloid accumulation in microvessels of aged rats. In this review, we focus on the detrimental effects of eNOS expression following brain embolism and introduce an attractive model representing progressive Alzheimer’s disease pathology in brain. Keywords:: microsphere embolism, nitric oxide (NO), calmodulin, endothelial nitric oxide synthase (eNOS), peroxynitrite, β-amyloid |
url |
http://www.sciencedirect.com/science/article/pii/S1347861319311089 |
work_keys_str_mv |
AT fenghan bamyloidaccumulationinneurovascularunitsfollowingbrainembolism AT kohjifukunaga bamyloidaccumulationinneurovascularunitsfollowingbrainembolism |
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