Inducible Nitric Oxide Synthase Gene Expression in Vascular Cells After Transient Focal Cerebral Ischemia

Iadecola, Costantino; Zhang, Fangyi; Casey, Robyn; Clark, H. Brent; Ross, M. Elizabeth

doi:10.1161/01.str.27.8.1373

Cited by 303 publications

(173 citation statements)

References 42 publications

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“…3 Obvious movements of one or more joints in both hind limbs but no forward propulsive, stepping movements. 4 Stepping and forward propulsive movements of one hind limb. No weight-bearing ability.…”

Section: Discussionmentioning

confidence: 99%

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Improved functional outcome after spinal cord injury in iNOS-deficient mice

2004

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Study design: Functional outcome was evaluated following experimental compression-type spinal cord injury (SCI) in wild-type mice and knockout mice, lacking the inducible nitric oxide synthase (iNOS) gene. Objectives: To evaluate the role of the nitric oxide generating enzyme iNOS in SCI. Methods: The experimental animals were subjected to an extradural compression of the thoracic spinal cord. Functional outcome was studied during the first 2 weeks post-injury using a scoring system for assessment of hind limb motor function. Results: Injury resulted in initial paraplegia followed by gradual improvement of motor function in most cases. Mice lacking the iNOS gene (iNOSÀ/À) clearly tended to have a better functional outcome than wild-type mice. The difference was significant on day 14 after injury. Conclusion: In accordance with a few earlier experimental studies, showing beneficial effects of pharmacological iNOS inhibition, the present report would indicate a destructive influence of iNOS following spinal cord trauma.

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Section: Discussionmentioning

confidence: 99%

“…4,5 Based on the findings obtained with pharmacological inhibition of NOS or comparisons between NOS-deficient and wildtype mice, both protective 3,6 and harmful [3][4][5] effects of NO in experimental CNS injury have been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Improved functional outcome after spinal cord injury in iNOS-deficient mice

2004

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“…Due to its vascular effect, NO, at physiological level, improves tissue perfusion and exert a protective action and reduced bioavailability of NO is thought to be one of the central factors common to vascular diseases. However, overproduction, either by activation of nNOS by excitatory [53], or by induction of iNOS in glial, vascular or blood cells [54][55][56] might be deleterious, which is especially true if combined with concurrent increases in free radical production. For example, excess NO production is found during excitotoxicity, inflammation and ischemia reperfusion injury [57] and it is known that NO can react with superoxide and the reaction is approximately six-times faster than the dismutation of superoxide by superoxide dismutase (SOD) [58].…”

Section: Nitric Oxide Malfunction and Vascular Oxidative Stress In Almentioning

confidence: 99%

Vascular oxidative stress in Alzheimer disease

Zhu

Smith

Honda

et al. 2007

Journal of the Neurological Sciences

160

156

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Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process. KeywordsAlzheimer disease; hypoperfusion; mitochondria; nitric oxide; nitric oxide synthase; oxidative stress; vascular abnormalitiesCorrespondence to: George Perry, Ph.D., College of Sciences, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, Texas 78249-0661 USA, , george.perry@utsa.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. . Therefore, perivascular Aβ deposits may be a risk factor for reduced regional CBF [7]. Ultrastructural studies on blood vessels associated with Aβ deposits have shown their intermittent association with membrane abnormalities of smooth muscle cells [5]. Indeed, in AD cases with a clinical history of cerebral bleeding, the muscle layer is sometimes completely replaced by Aβ deposits, suggesting that the vascular system may be an initiator for the development of diseas...

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“…The OD of the bands was determined by a gel image analysis system (Molecular Analyst; Bio-Rad). In some studies, measurements were normalized to the OD of the PBD band used as an internal standard (28,41).…”

Section: Reverse Transcription-pcr (Rt-pcr)mentioning

confidence: 99%

Reduced susceptibility to ischemic brain injury and N -methyl- d -aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice

Iadecola

Niwa

Nogawa

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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399

335

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Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in the brain injury produced by occlusion of the middle cerebral artery. The protection can be attributed to attenuation of glutamate neurotoxicity, a critical factor in the initiation of ischemic brain injury, and to abrogation of the deleterious effects of postischemic inflammation, a process contributing to the secondary progression of the damage. Thus, COX-2 is involved in pathogenic events occurring in both the early and late stages of cerebral ischemia and may be a valuable therapeutic target for treatment of human stroke.middle cerebral artery occlusion ͉ prostanoids ͉ cerebral blood flow ͉ NS398 ͉ stroke

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Inducible Nitric Oxide Synthase Gene Expression in Vascular Cells After Transient Focal Cerebral Ischemia

Cited by 303 publications

References 42 publications

Improved functional outcome after spinal cord injury in iNOS-deficient mice

Improved functional outcome after spinal cord injury in iNOS-deficient mice

Vascular oxidative stress in Alzheimer disease

Reduced susceptibility to ischemic brain injury and N -methyl- d -aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice

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