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

The associations of dietary folate, vitamin B(6), vitamin B(12), and methionine intakes with risk of stroke subtypes were examined among 26,556 male Finnish smokers, aged 50-69 years, enrolled in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Dietary intake was assessed at baseline by using a validated food frequency questionnaire. During a mean follow-up of 13.6 years, from 1985 through 2004, 2,702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were identified from national registers. In analyses adjusting for age and cardiovascular risk factors, a high folate intake was associated with a statistically significant lower risk of cerebral infarction but not intracerebral or subarachnoid hemorrhages. The multivariate relative risk of cerebral infarction was 0.80 (95% confidence interval: 0.70, 0.91; p(trend) = 0.001) for men in the highest versus lowest quintile of folate intake. Vitamin B(6), vitamin B(12), and methionine intakes were not significantly associated with any subtype of stroke. These findings in men suggest that a high dietary folate intake may reduce the risk of cerebral infarction.
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PMID:Folate, vitamin B6, vitamin B12, and methionine intakes and risk of stroke subtypes in male smokers. 1827 Mar 69

Cardiovascular pathologies in the French are not prevalent despite high dietary saturated fat consumption. This is commonly referred to as the "French Paradox" attributing its anti-lipidemic effects to moderate consumption of red wine. Resveratrol, a phytoalexin found in red wine, is currently the focus of intense research both in the cardiovascular system and the brain. Current research suggests resveratrol may enhance prognosis of neurological disorders such as, Parkinson's, Huntington's, Alzheimer's diseases and stroke. The beneficial effects of resveratrol include: antioxidation, free radical scavenger, and modulation of neuronal energy homeostasis and glutamatergic receptors/ion channels. Resveratrol directly increases sirtuin 1 (SIRT1) activity, a NAD(+) (oxidized form of nicotinamide adenine dinucleotide)-dependent histone deacetylase related to increased lifespan in various species similar to calorie restriction. We recently demonstrated that brief resveratrol pretreatment conferred neuroprotection against cerebral ischemia via SIRT1 activation. This neuroprotective effect produced by resveratrol was similar to ischemic preconditioning-induced neuroprotection, which protects against lethal ischemic insults in the brain and other organ systems. Inhibition of SIRT1 abolished ischemic preconditioning-induced neuroprotection in CA1 region of the hippocampus. Since resveratrol and ischemic preconditioning-induced neuroprotection require activation of SIRT1, this common signaling pathway may provide targeted therapeutic treatment modalities as it relates to stroke and other brain pathologies. In this review, we will examine common signaling pathways, cellular targets of resveratrol, and ischemic preconditioning-induced neuroprotection as it relates to the brain.
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PMID:Resveratrol and ischemic preconditioning in the brain. 1853 30

In pharmacological doses, nicotinic acid (niacin) reduces myocardial infarction, stroke and atherosclerosis. The beneficial effects of niacin on lipoproteins are thought to mediate these effects. We hypothesized that niacin inhibits oxidative stress and redox-sensitive inflammatory genes that play a critical role in early atherogenesis. In cultured human aortic endothelial cells (HAEC), niacin increased nicotinamide adenine dinucleotide phosphate (NAD(P)H) levels by 54% and reduced glutathione (GSH) by 98%. Niacin inhibited: (a) angiotensin II (ANG II)-induced reactive oxygen species (ROS) production by 24-86%, (b) low density lipoprotein (LDL) oxidation by 60%, (c) tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activation by 46%, vascular cell adhesion molecule-1 (VCAM-1) by 77-93%, monocyte chemotactic protein-1 (MCP-1) secretion by 34-124%, and (d) in a functional assay TNF-alpha-induced monocyte adhesion to HAEC (41-54%). These findings indicate for the first time that niacin inhibits vascular inflammation by decreasing endothelial ROS production and subsequent LDL oxidation and inflammatory cytokine production, key events involved in atherogenesis. Initial data presented herein support the novel concept that niacin has vascular anti-inflammatory and potentially anti-atherosclerotic properties independent of its effects on lipid regulation.
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PMID:Niacin inhibits vascular oxidative stress, redox-sensitive genes, and monocyte adhesion to human aortic endothelial cells. 1855 65

To assess whether azelnidipine (AZN) exerts renoprotective effects, 20-week-old adult male stroke-prone spontaneously hypertensive rats (SHRsp) were treated with AZN 10 mg/kg/d (n=6), olmesartan (OLM) 3 mg/kg/d (n=4), hydralazine (HYD) 20 mg/kg/d (n=3), or water (control; n=5). Each test agent was administered by oral gavage for 12 weeks. Systolic blood pressure (SBP) was measured every 2 weeks and urinary protein excretion (UproV) every 3 weeks. At the age of 32 weeks, the rats were sacrificed and blood and kidneys collected for biochemical, histological, and immunohistochemical studies. All drug treatments significantly (p<0.05) reduced SBP, UproV, and blood biochemical parameters such as creatinine, total cholesterol, and blood urea nitrogen. Masson trichrome staining and immunohistochemical staining revealed significant (p<0.05) reductions of interstitial fibrosis, collagen type III, nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase, and p22(phox) and p47(phox) components expression in the AZN- and OLM-treated groups in comparison with rats treated with HYD and control animals. ED1, 4-hydroxy-2-nonenal (4-HNE), and heat shock protein (HSP)-47 expression was also reduced in the AZN- and OLM-treated groups versus in HYD and control animals. These results indicate that not only OLM but also AZN exerts renoprotective effects through inhibition of macrophage infiltration and antioxidant activity in SHRsp model of renal injury.
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PMID:Renoprotective effect of azelnidipine in rats. 1904 6

Neurons require large amounts of energy to support their survival and function, and are therefore susceptible to excitotoxicity, a form of cell death involving bioenergetic stress that may occur in several neurological disorders including stroke and Alzheimer's disease. Here we studied the roles of NAD(+) bioenergetic state, and the NAD(+)-dependent enzymes SIRT1 and PARP-1, in excitotoxic neuronal death in cultured neurons and in a mouse model of focal ischemic stroke. Excitotoxic activation of NMDA receptors induced a rapid decrease of cellular NAD(P)H levels and mitochondrial membrane potential. Decreased NAD(+) levels and poly (ADP-ribose) polymer (PAR) accumulation in nuclei were relatively early events (<4 h) that preceded the appearance of propidium iodide- and TUNEL-positive cells (markers of necrotic cell death and DNA strand breakage, respectively) which became evident by 6 h. Nicotinamide, an NAD(+) precursor and an inhibitor of SIRT1 and PARP1, inhibited SIRT1 deacetylase activity without affecting SIRT1 protein levels. NAD(+) levels were preserved and PAR accumulation and neuronal death induced by excitotoxic insults were attenuated in nicotinamide-treated cells. Treatment of neurons with the SIRT1 activator resveratrol did not protect them from glutamate/NMDA-induced NAD(+) depletion and death. In a mouse model of focal cerebral ischemic stroke, NAD(+) levels were decreased in both the contralateral and ipsilateral cortex 6 h after the onset of ischemia. Stroke resulted in dynamic changes of SIRT1 protein and activity levels which varied among brain regions. Administration of nicotinamide (200 mg/kg, i.p.) up to 1 h after the onset of ischemia elevated brain NAD(+) levels and reduced ischemic infarct size. Our findings demonstrate that the NAD(+) bioenergetic state is critical in determining whether neurons live or die in excitotoxic and ischemic conditions, and suggest a potential therapeutic benefit in stroke of agents that preserve cellular NAD(+) levels. Our data further suggest that, SIRT1 is linked to bioenergetic state and stress responses in neurons, and that under conditions of reduced cellular energy levels SIRT1 enzyme activity may consume sufficient NAD(+) to nullify any cell survival-promoting effects of its deacetylase action on protein substrates.
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PMID:Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. 1928 25

In the present study, memantine (MN) an uncompetitive N-methyl-D-aspartate (NMDA) open channel blocker has been investigated for its suitable therapeutic time-window on the basis of its influence on behavioural and biochemical changes in rats subjected to transient focal ischemia. MN (20 mg/kg, ip) was administered at pre, during and post ischemic state and the extent of neuroprotection was compared to ascertain its therapeutic time-window in stroke treatment. Neuroprotective effect was assessed by measuring glutamate, glutamine synthetase, glutathione, Na+K+ATPase, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD), lactate and pyruvate levels. Middle cerebral artery occlusion produced neurological deficits, anxiogenic behaviour, histological changes, increased glutamate levels along with depletion of Na+K+ATPase, energy stores such as ATP, NAD, lactate, and antioxidant glutathione. MN significantly restored glutamate, glutamine synthetase, Na+K+ATPase and lactate levels on preischemic administration. In addition, MN reversed the altered neurological and behavioural paradigms significantly and prevented the neurodegeneration on preischemic treatment. However, it failed to exert any effect on energy metabolite (ATP and NAD) levels irrespective of the treatment phase. Based on the present data, it is summarized that the suitable therapeutic time window of MN is preischemic phase in stroke and it possesses only a subjective role in reversing ischemic brain biochemical alterations preferentially in favor of neuronal homeostasis.
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PMID:Pre-ischemic treatment with memantine reversed the neurochemical and behavioural parameters but not energy metabolites in middle cerebral artery occluded rats. 1946 56

Oxidative stress in the rostral ventrolateral medulla (RVLM) increases sympathetic nervous system activity (SNA). Oral treatment with atorvastatin decreases SNA through antioxidant effects in the RVLM of stroke-prone spontaneously hypertensive rats (SHRSP). We aimed to examine whether centrally administered atorvastain reduces SNA in SHRSP and, if so, to determine whether it is associated with the reduction of oxidative stress induced by alteration of activities of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase and superoxide dismutase (SOD) in the RVLM of SHRSP. SHRSP received atorvastatin (S-ATOR) or vehicle (S-VEH) by continuous intracerebroventricular infusion for 14 days. Mean blood pressure, heart rate, and SNA were significantly lower in S-ATOR than in S-VEH. Oxidative stress, Rac1 activity, NAD(P)H oxidase activity, Rac1, gp91(phox) and p22(phox) expression in the membrane fraction, and p47(phox) and p40(phox) expression in the cytosolic fraction in the RVLM were significantly lower in S-ATOR than in S-VEH. Rac1 expression in the cytosolic fraction and Mn-SOD activity, however, were significantly higher in S-ATOR than in S-VEH. Our findings suggest that centrally administered atorvastatin decreases SNA and is associated with decreasing NAD(P)H oxidase activity and upregulation of Mn-SOD activity in the RVLM of SHRSP, leading to suppressing oxidative stress.
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PMID:Sympathoinhibition induced by centrally administered atorvastatin is associated with alteration of NAD(P)H and Mn superoxide dismutase activity in rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats. 2004 Aug 88

Niacin (vitamin B(3)) is required to form nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are involved in scores of anabolic and catabolic redox reactions throughout metabolism. It is now understood that NAD(+) is also a substrate for several families of ADP-ribosylation reactions, which control processes like DNA repair, replication and transcription, the activity of G-proteins, chromatin structure and intracellular calcium signalling. Poly(ADP-ribose)polymerase-1 (PARP-1) is the most active of the PARP enzymes, and it has been implicated in both prevention and aggravation of disease processes. Inhibition of poly-ADP-ribose formation will tend to cause genomic instability and tumorigenesis in chronic models of DNA damage, but the same inhibition can prevent many acute disease processes, such as stroke, myocardial infarction and septic shock. In models of acute stress, PARP-1 inhibition may protect cellular NAD pools and prevent nuclear factor-kappaB-dependent inflammatory signalling, while long-term protective roles for PARP-1 include DNA repair and regulation of chromatin structure. Promising new PARP-1 inhibitors may display interactions with dietary niacin status and may have long-term deleterious effects on genomic stability, but may be extremely valuable for the treatment of acute inflammatory conditions.
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PMID:Poly ADP-ribose polymerase-1 and health. 2046 95

Poly(ADP-ribose) polymerases (PARPs) are a family of cell signaling enzymes present in eukaryotes, which are involved in the poly(ADP-ribosylation) of DNA binding proteins. While an 18 member superfamily of PARPs has been identified, however PARP-1 the most abundant isoform accounts for more than 90% of its functions. PARP-1 works as DNA damage nick sensor, which uses NAD(+) to form polymers of ADP-ribose (PAR) and nicotinamide. Three consequences of the activation of PARP-1 are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of proinflammatory genes. Consequently, pharmacological inhibition of PARP has the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). Through this article we have tried to develop a brief and simplified picture of the principal physiological and pathophysiological roles governed by PARP-1 and its therapeutic implications.
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PMID:Poly(ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications. 2063 99

Multiple cell death pathways are activated in cerebral ischaemia. Much of the initial injury, especially in the core of the infarct where cerebral blood flow is severely reduced, is necrotic and secondary to severe energy failure. However, there is considerable evidence that delayed cell death continues for several days, primarily in the penumbral region. As reperfusion therapies grow in number and effectiveness, restoration of blood flow early after injury may lead to a shift towards apoptosis. It is important to elucidate what are the key mediators of apoptotic cell death after stroke, as inhibition of apoptosis may have therapeutic implications. There are two well described pathways that lead to apoptotic cell death; the caspase pathway and the more recently described caspase-independent pathway triggered by poly-ADP-ribose polymers (PARP) activation. Caspase-induced cell death is initiated by release of mitochondrial cytochrome c, formation of the cytosolic apoptosome, and activation of endonucleases leading to a multitude of small randomly cleaved DNA fragments. In contrast caspase-independent cell death is secondary to activation of apoptosis inducing factor (AIF). Mitochondrial AIF translocates to the nucleus, where it induces peripheral chromatin condensation, as well as characteristic high-molecular-weight (50 kbp) DNA fragmentation. Although caspase-independent cell death has been recognized for some time and is known to contribute to ischaemic injury, the upstream triggering events leading to activation of this pathway remain unclear. The two major theories are that ischaemia leads to nicotinamide adenine dinucleotide (NAD+) depletion and subsequent energy failure, or alternatively that cell death is directly triggered by a pro-apoptotic factor produced by activation of the DNA repair enzyme PARP. PARP activation is robust in the ischaemic brain producing variable lengths of poly-ADP-ribose (PAR) polymers as byproducts of PARP activation. PAR polymers may be directly toxic by triggering mitochondrial AIF release independently of NAD+ depletion. Recently, sex differences have been discovered that illustrate the importance of understanding these molecular pathways, especially as new therapeutics targeting apoptotic cell death are developed. Cell death in females proceeds primarily via caspase activation whereas caspase-independent mechanisms triggered by the activation of PARP predominate in the male brain. This review summarizes the current literature in an attempt to clarify the roles of NAD+ and PAR polymers in caspase-independent cell death, and discuss sex specific cell death to provide an example of the possible importance of these downstream mediators.
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PMID:NAD+ depletion or PAR polymer formation: which plays the role of executioner in ischaemic cell death? 2109 37


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