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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biosynthesis of oxygenated arachidonic acid messengers triggered by cerebral ischemia-reperfusion is preceded by an early and rapid phospholipase A2 activation reflected in free arachidonic and docosahexaenoic acid (DHA) accumulation. These fatty acids are released from membrane phospholipids. Both fatty acids are derived from dietary essential fatty acids; however, only DHA, the omega-3 polyunsaturated fatty acyl chain, is concentrated in phospholipids of various cells of brain and retina. Synaptic membranes and photoreceptors share the highest content of DHA of all cell membranes. DHA is involved in memory formation, excitable membrane function, photoreceptor cell biogenesis and function, and neuronal signaling, and has been implicated in neuroprotection. In addition, this fatty acid is required for retinal pigment epithelium cell (RPE) functional integrity. Here we provide an overview of the recent elucidation of a specific mediator generated from DHA that contributes at least in part to its biological significance. In oxidative stress-challenged human RPE cells and rat brain undergoing ischemia-reperfusion, 10,17S-docosatriene (neuroprotectin D1, NPD1) synthesis evolves. In addition, calcium ionophore A23187, IL-1beta, or the supply of DHA enhances NPD1 synthesis. A time-dependent release of endogenous free DHA followed by NPD1 formation occurs, suggesting that a phospholipase A2 releases the mediator's precursor. When NPD1 is infused during ischemia-reperfusion or added to RPE cells during oxidative stress, apoptotic DNA damage is down-regulated. NPD1 also up-regulates the anti-apoptotic Bcl-2 proteins Bcl-2 and BclxL and decreases pro-apoptotic Bax and Bad expression. Moreover, NPD1 inhibits oxidative stress-induced caspase-3 activation. NPD1 also inhibits IL-1beta-stimulated expression of COX-2. Overall, NPD1 protects cells from oxidative stress-induced apoptosis. Because photoreceptors are progressively impaired after RPE cell damage in retinal degenerative diseases, understanding of how these signals contribute to retinal cell survival may lead to the development of new therapeutic strategies. Moreover, NPD1 bioactivity demonstrates that DHA is not only a target of lipid peroxidation, but rather is the precursor to a neuroprotective signaling response to ischemia-reperfusion, thus opening newer avenues of therapeutic exploration in stroke, neurotrauma, spinal cord injury, and neurodegenerative diseases, such as Alzheimer disease, aiming to up-regulate this novel cell-survival signaling.
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PMID:Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. 1591 89

The objective of this review is to summarize the literature on Alzheimer's disease progression utilizing cognitive batteries to track change over time. Studies published in English and obtained through PubMed searches (1983-2004) were included (i) if they had a longitudinal design and followed probable Alzheimer's patients diagnosed by National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association or Diagnostic and Statistical Manual III/IV criteria, and (ii) if the techniques used for serial assessment were well-established in terms of validity and reliability. Longitudinal studies examining Alzheimer's disease progression report highly variable annual rates of change in decline rate. It remains unclear if this reflects disease subgroups or stage-related rate of decline. In conclusion a combination of stage-appropriate cognitive tests such as the Mattis Dementia Rating Scale and the Severe Impairment Battery, along with appropriate statistical methods to account for individual variability in decline rates, can capture the progression of Alzheimer disease and may be useful in further investigation.
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PMID:Progress in clinical neurosciences: cognitive markers of progression in Alzheimer's disease. 1601 49

Redox stress activates the endothelium and upregulates matrix metalloproteinases (MMPs), which degrade the matrix and lead to blood-endothelial barrier leakage. Interestingly, elevated levels of plasma homocysteine (Hcy) are associated with vascular dementia, seizure, stroke, and Alzheimer disease. Hcy competes with the gamma-aminobutyric acid (GABA)-A/B receptors and behave like an excitatory neurotransmitter. GABA stimulates the inhibitory neurotransmitter GABA-A/B receptor and decreases arterial blood pressure. However, the neural mechanisms of microvascular remodeling in hyperhomocysteinemia are unclear. This review addresses the idea that Hcy induces microvascular permeability by attenuating the GABA-A/B receptors and increasing redox stress, which activates a disintegrin and metalloproteinase that suppresses tissue inhibitors of metalloproteinase. This process causes disruption of the matrix in the blood-brain barrier. Understanding the mechanism of Hcy-mediated changes in permeability of the blood-brain barrier and extracellular matrix that can alter the neuronal environment in cerebral-vascular dementia is of great importance in developing treatments for this disease.
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PMID:Homocysteine in microvascular endothelial cell barrier permeability. 1604 81

The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.
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PMID:Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. 1635 86

Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular beta-amyloid (Abeta) in the walls of arterial vessels, has been implicated in hemorrhagic stroke and is present in most cases of Alzheimer disease. Previous studies of the progression of CAA in humans and animal models have been limited to the comparison of pathological tissue from different brains at single time points. Our objective was to visualize in real time the initiation and progression of CAA in Tg2576 mice by multiphoton microscopy through cranial windows. Affected vessels were labeled by methoxy-X04, a fluorescent dye that selectively binds cerebrovascular beta-amyloid and plaques. With serial imaging sessions spaced at weekly intervals, we were able to observe the earliest appearance of CAA in leptomeningeal arteries as multifocal deposits of band-like Abeta. Over subsequent imaging sessions, we were able to identify growth of these deposits (propagation), as well as appearance of new bands (additional initiation events). Statistical modeling of the data suggested that as the extent of CAA progressed in this vascular bed, there was increased prevalence of propagation over initiation. During the early phases of CAA development, the overall pathology burden progressed at a rate of 0.35% of total available vessel area per day (95% confidence interval, 0.3-0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions.
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PMID:Kinetics of cerebral amyloid angiopathy progression in a transgenic mouse model of Alzheimer disease. 1640 31

Neurogenesis, or the production of new neurons from neuronal precursor cells, is a normal phenomenon in the adult brain, and is accentuated by brain injury. Forms of injury associated with increased neurogenesis include both acute (e.g., stroke) and chronic neurodegenerations. Studies on human postmortem material and transgenic mice overexpressing amyloid precursor protein mutations found in familial Alzheimer's disease (AD) suggest that AD is associated with enhanced neurogenesis. However, the mechanism responsible for this effect is unknown, as is what influence it may have on the clinical course of murine or human AD. If AD leads to the production of fully functional, mature neurons that can restore brain function, strategies aimed at further increasing endogenous neurogenesis may have therapeutic value.
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PMID:Neurodegeneration and neurogenesis: focus on Alzheimer's disease. 1647 99

Low serum potassium increases risk of hypertension and stroke, and cardiovascular factors increase the risk of Alzheimer disease (AD). We examined the association between serum potassium and the biologic marker cerebrospinal fluid amyloid-beta (Abeta42), which is decreased in Alzheimer disease patients. Psychiatric examinations, laboratory and other tests were conducted on a population-based sample of 1080 women aged 46 to 60 in 1968, with follow-ups in 1974, 1980, and 1992. In 1992, cerebrospinal fluid Abeta42 levels were obtained from 81 women. Increasing serum potassium in 1968 was associated with increasing cerebrospinal fluid Abeta42 (beta = 153.9, P = 0.041) in 1992 using age-adjusted linear regression. Compared with the lowest tertile of potassium, the middle (beta = 95.3, P = 0.138) and highest tertiles (beta = 193.5, P = 0.004) had incrementally increased cerebrospinal fluid Abeta42 levels. Associations remained after controlling for blood pressure and other factors, and were similar among the 17 women in 1974 with available serum potassium. Potassium in 1980 and 1992 was not associated with cerebrospinal fluid Abeta42. Findings suggest low serum potassium in mid life, but not late life, is associated with low cerebrospinal fluid Abeta42 levels in late life. It is possible potassium co-varies with another variable that is associated with cerebrospinal fluid Abeta42. Nonetheless, serum potassium is a modifiable risk factor and further examination of the potassium-dementia relationship is warranted.
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PMID:Low serum potassium in mid life associated with decreased cerebrospinal fluid Abeta42 in late life. 1649 33

Aging is characterized by widespread degenerative changes in tissue morphology and function and an increase in the incidence of human diseases such as cancer, stroke, and Alzheimer disease. Findings from recent genetic studies suggest that molecular mechanisms that influence life span are evolutionarily conserved, and interventions that extend the life span of model organisms such as worms and flies are likely to have similar effects on vertebrates such as humans. However, little progress has been made in identifying drugs that delay aging. We identified 3 pharmacologic compounds, ethosuximide, trimethadione, and 3,3-diethyl-2-pyrrolidinone, that extend lifespan and delay age-related degenerative changes in the nematode worm Caenorhabditis elegans. All 3 compounds are anticonvulsants that modulate neural activity in vertebrates, and ethosuximide and trimethadione are used to treat absence seizures in humans. We discuss existing evidence that these drugs might also delay vertebrate aging and suggest experiments that could test this hypothesis. Genetic and cell ablation studies conducted with model organisms have demonstrated connections between the nervous system and aging. Our studies provide additional support for the hypothesis that neural activity plays a role in lifespan determination, since ethosuximide and trimethadione regulated neuromuscular activity in nematodes. Our findings suggest that the lifespan extending activity of these compounds is related to the anticonvulsant activity, implicating neural activity in the regulation of aging. We also discuss models that explain how the nervous system influences lifespan.
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PMID:Effects of anticonvulsant drugs on life span. 1660 60

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. Peptide activity scanning identified NAP (NAPVSIPQ) as a small active fragment of ADNP that provides neuroprotection at very low concentrations. In cell culture, NAP has demonstrated protection against toxicity associated with the beta-amyloid peptide, N-methyl-D-aspartate, electrical blockade, the envelope protein of the AIDS virus, dopamine, H2O2, nutrient starvation and zinc overload. NAP has also provided neuroprotection in animal models of apolipoprotein E deficiency, cholinergic toxicity, closed head injury, stroke, middle aged anxiety and cognitive dysfunction. NAP binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. A liquid-chromatography, mass spectrometry assay demonstrated that NAP reaches the brain after either intravenous or intranasal administration. In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs, and functional behavioral assays in rats, no adverse side effects were observed with NAP concentrations that were approximately 500-fold higher than the biologically active dose. A Phase Ia clinical trial in the US assessed the tolerability and pharmacokinetics of intranasal administration of NAP in sequential ascending doses. The results supported the safety and tolerability of a single dose of NAP administered at up to 15 mg intranasally. Furthermore, dosing was recently completed for a second Phase I clinical trial in healthy adults and elderly volunteers with an intravenous formulation of NAP. NAP is poised for further clinical development targeting several indications, including Alzheimer's disease.
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PMID:NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP). 1661 35

Estrogens are gonadal steroid hormones that are present in the circulation of both males and females and that can no longer be considered within the strict confines of reproductive function. In fact, the bone, the cardiovascular system, and extrahypothalamic regions of the brain are now well-established targets of estrogens. Among the numerous aspects of brain function regulated by estrogens are their effects on mood, cognitive function, and neuronal viability. Here, we review the supporting evidence for estrogens as neuroprotective agents and summarize the various mechanisms that may be involved in this effect, focusing particularly on the mitochondria as an important target. On the basis of this evidence, we discuss the clinical applicability of estrogens in treating various age-related disorders, including Alzheimer disease and stroke, and identify the caveats that must be considered.
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PMID:Novel mechanisms for estrogen-induced neuroprotection. 1663 99


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