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

Sphingomyelin and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. At the epicenter of the sphingomyelin--cell signaling pathway is a family of phospholipases called sphingomyelinases. These enzymes cleave sphingomyelin to produce ceramide and phosphocholine. Ceramide in turn serves as a lipid second messenger that induces a variety of cell regulatory phenomenon such as programmed cell death (apoptosis), cell differentiation, cell proliferation, and sterol homeostasis. Neutral sphingomyelinase (N-SMase) is a Mg2+ sensitive enzyme that can be activated by a host of physiologically relevant and structurally diverse molecules like tumor necrosis factor-alpha (TNF-alpha), oxidized human low density lipoproteins (Ox-LDL), and several growth factors. Large amounts of ceramide accumulate in human fatty streaks and plaques along with Ox-LDL, growth factors, and proinflammatory cytokines in human atherosclerosis. A further role of ceramide and N-SMase in atherosclerosis was uncovered by the finding that Ox-LDL and TNF-alpha stimulated N-SMase activity. In turn, ceramide and/or a homolog serves as an important stress signaling molecule in signal transduction, which leads to apoptosis. Interestingly, an antibody against N-SMase can abrogate Ox-LDL and TNF-alpha induced apoptosis, and therefore may be useful for additional studies of apoptosis in experimental animals. Overexpression of recombinant human N-SMase in human aortic smooth muscle cells markedly stimulate apoptosis, presumably via the multioligomerization of the 'death domain'. Since plaque stability is an integral aspect of atherosclerosis management, activation of N-SMase and subsequent apoptosis may be vital events in the onset of plaque rupture, stroke and heart failure. In contrast to these observations in human hepatocytes, TNF-alpha mediated N-SMase activation did not induce apoptosis. Rather it stimulated the maturation of sterol regulatory element (SRE) binding protein (SREBP-1). Moreover, a cell permeable ceramide was found to reconstitute the phenomenon above in a sterol-independent fashion. These findings provide alternate avenues for therapy of patients with hypercholesterolemia and atherosclerosis. The findings reported here suggests that N-SMase plays important cell regulatory roles and provide an exciting opportunity to further these findings to understand the pathophysiology of human disease states.
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PMID:Neutral sphingomyelinase: past, present and future. 1100 63

Clinically, it is known that: (1) magnesium (Mg) supplementation relieves premenstrual problems (e.g., migraine, bloating and edema) occurring in the late luteal phase of the menstrual cycle; and (2) migraine syndromes, particularly in women, are associated with deficits in brain and serum ionized Mg levels. We investigated whether concentrations of sex steroid hormones, found in the serum during the menstrual cycle of women, are associated with changes in the levels of cytosolic free magnesium ions ([Mg2+]i in single cultured canine cerebral vascular smooth muscle cells. The resting level of [Mg2+]i in these cells was 645 +/- 89 microM before exposure to sex steroid hormones. Exposure of these vascular cells to a low concentration of estrogen (10 pg/ml) failed to interfere with the levels of [Mg2+]i. However, exposure to estrogen, at concentrations ranging from 40 to 200 pg/ml, induced significant loss of [Mg2+]i in a concentration-dependent manner. At a concentration of 200 pg/ml estrogen, the level of [Mg2+]i decreased approximately 30% in comparison with controls. Progesterone produced biphasic effects on the levels of [Mg2+]i, depending on its concentration. Exposure of the cultured cells to a low concentration of progesterone (0.5 ng/ml) resulted in an increased level of [Mg2+]i (from 690 +/- 50 microM to 753 +/- 56 microM, p < 0.05). However, when these cells were exposed to higher concentrations of progesterone (i.e., from 5.0 to 20 ng/ml), the cellular levels of [Mg2+]i were decreased significantly. The higher the estrogen or progesterone concentration, the lower the levels of [Mg2+]i. In contrast, testosterone, a male hormone, didn't produce any significant alteration in [Mg2+]i levels in these cerebral vascular smooth muscle cells. These data indicate that low, physiological concentrations of female sex hormones, estrogen and progesterone, help cerebral vascular smooth cells sustain normal concentrations of [Mg2+]i, which are beneficial to vascular function, whereas high levels of estrogen and progesterone deplete, significantly, [Mg2+]i in cerebral vascular smooth muscle cells, possibly resulting in cerebrovasospasms and reduced cerebral blood flows related to premenstrual syndromes, migraine and stroke risk. Our findings could provide new insight into the mechanism whereby migraine occurs frequently in the late luteal phase in the premenstrual syndrome. In addition, our results demonstrate that female sex steroids but not testosterone (in physiologic concentrations) can exert direct effects on [Mg2+]i in cerebral vascular cells.
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PMID:Sex steroid hormones exert biphasic effects on cytosolic magnesium ions in cerebral vascular smooth muscle cells: possible relationships to migraine frequency in premenstrual syndromes and stroke incidence. 1122 17

Perturbation of normal survival mechanisms may play a role in a large number of disease processes. Glutamate neurotoxicity, particularly when mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, has been hypothesized to underlie several types of acute brain injury, including stroke. Several neurological insults linked to excessive release of glutamate and neuronal death result in tyrosine kinase activation, including p44/42 mitogen activated protein (MAP) kinase. To further explore a role for MAP kinase activation in excitotoxicity, we used a novel tissue culture model to induce neurotoxicity. Removal of the endogenous blockade by Mg2+ of the NMDA receptor in cultured hippocampal neurons triggers a self perpetuating cycle of excitotoxicity, which has relatively slow onset, and is critically dependent on NMDA receptors and activation of voltage gated Na+ channels. These injury conditions led to a rapid phosphorylation of p44/42 that was blocked by MAP kinase kinase (MEK) inhibitors. MEK inhibition was associated with protection against synaptically mediated excitotoxicity. Interestingly, hippocampal neurons preconditioned by a sublethal exposure to Mg(2+)-free conditions were rendered resistant to injury induced by a subsequently longer exposure to this insult; the preconditioning effect was MAP kinase dependent. The MAP kinase signaling pathway can also promote polypeptide growth factor mediated neuronal survival. MAP kinase regulated pathways may act to promote survival or death, depending upon the cellular context in which they are activated.
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PMID:Neuronal protein kinase signaling cascades and excitotoxic cell death. 1146 62

Clinical trials for ischemic stroke have been characterized by a disappointing series of negative results, using a panoply of pharmacologic agents. This paper emphasizes five physiologic measures that can be taken to mitigate ischemic brain damage. These are (1) hypothermia, (2) insulin, (3) arterial hyperoxemia, (4) blood pressure control and (5) magnesium. Hypothermia is protective in both focal and global ischemia, even postischemically protecting against selective neuronal necrosis and infarction. The total equation for protection includes the (i) postischemic delay, (ii) depth, and (iii) duration of hypothermia. Insulin operates by lowering glucose levels to the normal range in focal ischemia. It is possible that very low glucose levels are detrimental in focal ischemia with paradoxical augmentation of the infarct size, and that spreading depression plays a role in this. Controlled arterial hyperoxemia seems effective experimentally in reducing infarct size, operating mechanistically by either a direct effect of oxygen, or vasoconstriction causing shunting of blood into the infarct, or both. Blood pressure is a critical determinant of infarct size, and raising blood pressure improves collateral blood flow and reduces stroke size. To be used clinically, however, hemorrhage must be ruled out. The most dramatic clinical effects of blood pressure are seen in aneurysm patients with vasospasm, where minor increases in blood pressure reverse temporary hemiparesis by reducing ischemia. Magnesium is likely the safest NMDA antagonist, with a long history of safe administration to pregnant women with eclampsia. There is potential interaction with insulin, in that magnesium causes hyperglycemia, which requires insulin to counteract it. Magnesium and insulin together have been shown effective in experimental brain ischemia. In the absence of safe and effective pharmacologic neuroprotection agents, clinical trials should be designed and launched to test these physiologic measures, singly and in combination, to reduce brain damage after ischemia.
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PMID:Non-pharmacologic (physiologic) neuroprotection in the treatment of brain ischemia. 1146 80

Magnesium probably protects brain tissue against the effects of cerebral ischemia, brain injury and stroke through its actions as a calcium antagonist and inhibitor of excitatory amino acids. The effects of magnesium sulfate on cerebrovascular permeability to a dye, Evans blue, were studied during insulin-induced hypoglycemia with hypothermia in rats. Hypoglycemia was induced by an intramuscular injection of insulin. After giving insulin, each animal received MgSO4 (270 mg/kg) ip, followed by a 27 mg/kg dose every 20 min for 2.5 h. Plasma glucose and Mg2+ levels of animals were measured. Magnesium concentrations increased in the serum following MgSO4 administration (6.05+/-0.57 vs. 2.58+/-0.14 mg/dL in the Mg2+ group, and 7.14+/-0.42 vs. 2.78+/-0.06 mg/dL in the insulin + Mg2+ group, P < 0.01). Plasma glucose levels decreased following hypoglycemia (4+/-0.66 vs. 118+/-2.23 mg/dL in the insulin group, and 7+/-1.59 vs. 118+/-4.84 mg/dL in the insulin + Mg2+ group, P < 0.01). Blood-brain barrier permeability to Evans blue considerably increased in hypoglycemic rats (P < 0.01). In contrast, blood-brain barrier permeability to Evans blue was significantly reduced in treatment of hypoglycemic rats with MgSO4 (P < 0.01). These results indicate that Mg2+ greatly reduced the passage of exogenous vascular tracer bound to albumin into the brain during hypoglycemia with hypothermia. Mg2+ could have protective effects on blood-brain barrier permeability against insulin-induced hypoglycemia.
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PMID:Magnesium sulfate attenuates increased blood-brain barrier permeability during insulin-induced hypoglycemia in rats. 1159 80

The Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial is a multicentre,randomised, placebo-controlled trial of magnesium sulphate (MgSO4) funded by the UK Medical Research Council. When complete, it will be the largest single neuroprotective study undertaken to date. Conscious patients presenting within 12 h of acute stroke with limb weakness are eligible. The primary outcome measure is combined death and disability as measured using the Barthel Index at 90-day follow up. By randomizing 2700 patients, the study will have 84% power to detect a 5.5% absolute reduction in the primary end-point. By April 2000, 86 centres were participating, with representation in Canada, USA, Europe, South America, Singapore and Australia. So far, 1206 patients have been randomised, of whom 37% were treated within 6 h. Overall 3-month mortality was 20% and the primary outcome event rate was 43%. The study is ongoing and centres worldwide are encouraged to participate.
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PMID:Design of the Intravenous Magnesium Efficacy in Acute Stroke (IMAGES) trial. 1171 36

Magnesium exhibits a range of neuronal and vascular actions that may ameliorate ischaemic CNS insults, including stroke. Significant neuroprotection with magnesium has been observed in different models of focal cerebral ischaemia in many laboratories, with infarct volume reductions between 25 and 61%. Maximal neuroprotection is evident at readily attainable serum concentrations, and neuroprotection is still seen when administration is delayed up to 6 hours after onset of ischaemia. Clinical use of magnesium in pre-eclampsia and acute myocardial infarction confirms its safety and tolerability. Five small trials in acute stroke have reported reduced odds of death or dependence with administration of magnesium, but confidence intervals are wide, and definitive data from ongoing large trials are awaited.
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PMID:Magnesium for neuroprotection in ischaemic stroke: rationale for use and evidence of effectiveness. 1173 12

Magnesium is involved in multiple physiological processes that may be relevant to cerebral ischaemia, including antagonism of glutamate release, NMDA receptor blockade, calcium channel antagonism, and maintenance of cerebral blood flow. Systemically administered magnesium at doses that double physiological serum concentration significantly reduces infarct volume in animal models of stroke, with a window of up to six hours after onset and favourable dose-response characteristics when compared with previously tested neuroprotective agents. Small clinical trials have reported benefit, but results are not statistically significant in systematic review. A large ongoing trial (IMAGES) will report in 2003-4 and further trials are planned.
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PMID:Magnesium in stroke treatment. 1249 16

Traditional Chinese medicine (TCM) has a long history in stroke therapy and its therapeutic efficacy has been confirmed by clinical studies. The molecular basis of the neuroprotective effects is unknown. We wondered whether or not the neuroprotective effect of TCMs might be due to their N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist properties. We used the patch-clamp technique to screen 22 TCM stroke drugs for NMDAR antagonist activity in cultured cortical neurons. The drugs were also screened for their ability to abate NMDA-induced neurotoxicity. Aqueous extracts of Scutellaria baicalensis, Stephania tetrandra, and Salvia miltiorrhiza blocked currents induced by NMDA (200 microM, 10 microM glycine, 0 Mg2+) at a holding potential of -80 mV by 83.45+/-4.34, 38.65+/-7.50, and 52.97+/-1.78%, respectively. The block of the NMDA-evoked currents was voltage-dependent and showed a negative slope conductance reminiscent of Mg2+. Atomic absorption spectrophotometry revealed the presence of 12.5, 2, and 8.7 mM Mg2+ in the extracts of S. baicalensis,S. tetrandra, and S. miltiorrhiza, respectively. None of these extracts blocked NMDA-induced neuronal death. The Uncaria rhynchophylla extract blocked NMDA-evoked currents by 54.98+/-8.61% even at +60 mV and reduced NMDA-induced neuronal death by 59.13+/-3.52%. NMDAR antagonist activity may underlie the neuroprotective effects of this TCM. Some TCM drugs may exert therapeutic effects due to their Mg2+ content.
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PMID:N-methyl-D-aspartate receptor antagonist activity in traditional Chinese stroke medicines. 1262 26

Major interest is currently focused on the development and evaluation of effective strategies for the pharmacological therapy of human stroke and cerebral ischemia, as well as some neurodegenerative disorders in which increased production of free oxygen radicals and the neurotoxic effect of excitatory amino acids may take place. Selected N-methyl-D-aspartate (NMDA) antagonists and antioxidants in the model of experimental oxidative stress induced by hypoxia and reoxygenation in rat hippocampal slices were tested. The putative antiglutamatergic effect of the antioxidant stobadine and its neuroprotective effect during oxidative stress was studied. NMDA antaonists 2-amino-5-phosphonovaleric acid (APV) and Mg2+, as well as the antioxidants stobadine and trolox, prevented the decrease of NMDA binding site number induced by hypoxia/reoxygenation in rat hippocampal slices. Moreover, stobadine, APV and Mg2+ prevented the decrease of NMDA binding site number due to glutamic acid incubation. Stobadine does not inhibit [3H]-glutamate binding and therefore does not seem to interact directly with glutamate binding sites. Thus, its neuroprotective effect in rat hippocampus exposed to hypoxia/reoxygenation does not seem to be based on a direct antiglutamatergic effect. The protective action of stobadine against the decrease of NMDA binding site number elicited by hypoxia/reoxygenation in rat hippocampus could rather be due to its antioxidant and antiradical effect.
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PMID:Effect of antioxidants and NMDA antagonists on the density of NMDA binding sites in rat hippocampal slices exposed to hypoxia/reoxygenation. 1269 Jul 2


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