Changes in Vessel Ultrastructure during Ischemia and Reperfusion of Rabbit Hindlimb: Implications for Therapeutic Intervention

Aliev, Gjumrakch; Cirillo, R; Salvatico, Estela; Paro, M.; Prosdocimi, Marco

doi:10.1006/mvre.1993.1035

Cited by 31 publications

(44 citation statements)

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“…Our observations demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress-induced damage before the development of AD pathology [45,46]. Notably, long-term ischemia/reperfusion leads to disintegration of mitochondria ultrastructure [47,48] and apoptosis of degenerating neurons occurs in association with the accumulation of perikaryal abnormal mitochondria and oxidative damage to the nucleus [49]. Likely not coincidentally, this same pattern of mitochondria lesions is observed in human AD brain biopsy samples [50].…”

Section: Vascular Oxidative Stress In Alzheimer Diseasementioning

confidence: 72%

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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Section: Vascular Oxidative Stress In Alzheimer Diseasementioning

confidence: 72%

Vascular oxidative stress in Alzheimer disease

Zhu

Smith

Honda

et al. 2007

Journal of the Neurological Sciences

160

156

View full text Add to dashboard Cite

show abstract

“…In addition, the mechanisms behind the effects of several vascular factors and peripheral vascular pathophysiology might promote the late-onset of AD (79,(87)(88)(89). Apolipoprotein E (ApoE), a major risk factor for atherosclerosis (8,90,91) as well as AD (92), may be linked to AD via its effects on the vasculature (6,7,67,93).…”

Section: Relationships Between Apoe Genotype Hypercholesterolemia Amentioning

confidence: 99%

“…The effect of acute ischemia and chronic neurodegenerative diseases on neuronal mitochondrial ultrastructure has been reviewed recently (103). After long-term ischemia/ reperfusion the mitochondrial ultrastructure disintegrates in vivo and in vitro (8,51,52). Apoptosis of degenerating neurons occurs in association with the accumulation of perikaryal mitochondria and oxidative damage to the nucleus (111).…”

Section: Relationships Between Apoe Genotype Hypercholesterolemia Amentioning

confidence: 99%

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Oxidative stress-induced mitochondrial failure and vasoactive substances as key initiators of pathology favor the reclassification of Alzheimer Disease as a vasocognopathy

Aliev

LaManna

Morales

et al. 2008

nova

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Alzheimer disease and cerebrovascular accident are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. Hypoperfusion is associated with oxidative imbalance, largely due to reactive oxygen species, which is associated with other age-related degenerative disorders. Recent evidence indicates that a chronic injury stimulus induces the hypoperfusion seen in the microcirculation of vulnerable regions of the brain. This leads to energy failure, manifested by damaged mitochondrial ultrastructure. Mitochondrial derangements lead to the formation of a large number of electron-dense, "hypoxic" mitochondria and cause the overproduction of mitochondrial DNA (mtDNA) deletions, which is most likely due to double stranded breaks. Additionally, these mitochondrial abnormalities coexist with increased redox metal activity, lipid peroxidation, and RNA oxidation, all of which are well established features of Alzheimer disease pathology, prior to the appearance of amyloid b deposition.Alzheimer disease, oxidative stress occurs within various cellular compartments and within certain cell types more than others, namely the vascular endothelium, which is associated with atherosclerotic damage, as well as in pyramidal neurons and glia. Interestingly, these vulnerable cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels. This evidence strongly suggests that chronic hypoperfusion induces the accumulation of the oxidative stress products. Furthermore, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage. We, therefore, conclude that chronic hypoperfusion is a key initiator of oxidative stress in various brain parenchymal cells, and the mitochondria appear to be primary targets for brain damage in Alzheimer disease. In this manuscript, we outline a role for the continuous accumulation of oxidative stress products, such as an abundance of nitric oxide products (via the overexpression of inducible and/or neuronal NO synthase (iNOS and nNOS respectively) and peroxynitrite accumulation, as secondary but accelerating factors compromising the blood brain barrier (BBB). If this turns out to be the case, pharmacological interventions that target chronic hypoperfusion might ameliorate the key features of dementing neurodegeneration.Key words: brain hypoperfusion, mitochondria, neurodegeneration, nitric oxide, oxidation, oxidative stress, vasoactive substances. ARTÍCULO DE REVISIÓN 171Resumen Falla mitocondrial oxidativa inducida por estrés y sustancias vasoactivas como los iniciadores dominantes de la patología favorecen la reclasificación de la enfermedad de Alzheimer como una VasocognopatíaLa enfermedad de Alzheimer y el accidente cerebrovascular son dos causas que conducen a la demencia relativa a la edad. El aumento de la evidencia apoya la idea de que la hipoperfusión crónica es sobr...

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“…The basis of low-frequency fatigue was subsequently shown to be a consequence of reduced calcium release from the sarcoplasmic reticulum, possible secondary to cellular damage that might impair efficient excitation-contraction coupling. Microcirculatory injury can also be observed during/following skeletal muscle ischaemia (Korthius, Grisham & Granger, 1988;Aliev, Cirillo, Salvatico, Paro & Prosdocimi, 1993). These changes may compromise blood flow to postischaemic regions and hinder recovery.…”

Section: Poor Recovery Offunction In the Control Groupmentioning

confidence: 99%

Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat

Wickenden¹,

Brooks²,

Kelly³

et al. 1997

Experimental Physiology

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SUMMARYThe aim of the present experiment was to determine whether the potassium channel opener 2-(2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine-4-yl)pyridine-N-oxide (ZM260384) was capable of' accelerating the decline in skeletal muscle function during restricted blood flow in vivo. Cats (3.0-4.5 kg body weight) were anaesthetized with alphaxalone-alphadalone and breathed spontaneously following tracheotomy. Isometric tension was measured in the extensor digitorum longus-anterior tibialis (EDL-TA) muscle group. Ischaemia was induced by perfusing the hindlimb with the animal's own blood at a rate of 12 5 ml min' using a roller pump and stimulating the common peroneal nerve to induce repetitive submaximal tetanic contractions in the EDL-TA. The number of stimulation voltage increments required each minute to maintain a constant level of submaximal mechanical output and the time to exhaustion were used as indices of the rate of tension decline. The rate of tension decline in the ischaemic EDL-TA in the presence of ZM260384 at 3 mg kg-', a maximally hypotensive dose predicted to be within the dose range required to exert direct effects on skeletal muscle, was measured and compared with the rate of tension decline in the presence of ZM260384 at 0 03 mg kg-', also a maximally hypotensive dose but below the predicted dose range for skeletal muscle effects. The number of voltage increments per minute was 1.93 + 0 07 and 1-48 + 0 14 (P < 0 05) in the presence of 3 and 0-03 mg kg ZM260384, respectively. Time to exhaustion was 17 5 + 4-2 and 7 2 + 0-8 min (P < 0-05) in the presence of 3 and 003 mg kg-IZM260384, respectively. Given that there was no difference between these two groups in any haemodynamic variable measured, the results of the present study suggest that ZM260384 (3 mg kg ') increases the rate of isometric force loss in ischaemic skeletal muscle in vivo.

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Changes in Vessel Ultrastructure during Ischemia and Reperfusion of Rabbit Hindlimb: Implications for Therapeutic Intervention

Cited by 31 publications

References 0 publications

Vascular oxidative stress in Alzheimer disease

Vascular oxidative stress in Alzheimer disease

Oxidative stress-induced mitochondrial failure and vasoactive substances as key initiators of pathology favor the reclassification of Alzheimer Disease as a vasocognopathy

Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat

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