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

Nefiracetam is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and post-stroke vascular-type dementia. In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems has been found and is thought to play an important role in impairment of cognition, learning and memory. We have previously shown that the activity of neuronal nicotinic acetylcholine receptors is potently augmented by nefiracetam. The present study was undertaken to elucidate the mechanism of action of nefiracetam on glutamatergic receptors. Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell patch-clamp technique at a holding potential of -70 mV in Mg2+-free solutions. N-Methyl-D-aspartate (NMDA)-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam resulting in a bell-shaped dose-response curve. The minimum effective nefiracetam concentration was 1 nM, and the maximum potentiation to 170% of the control was produced at 10 nM. Nefiracetam potentiation occurred at high NMDA concentrations that evoked the saturated response, and in a manner independent of NMDA concentrations ranging from 3 to 1,000 microM. Glycine at 3 microM potentiated NMDA currents but this effect was attenuated with an increasing concentration of nefiracetam from 1 to 10,000 nM. 7-Chlorokynurenic acid at 1 microM prevented nefiracetam from potentiating NMDA currents. Nefiracetam at 10 nM shifted the dose-response relationship for the 7-chlorokynurenic acid inhibition of NMDA currents in the direction of higher concentrations. Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- and kainate-induced currents were not significantly affected by application of 10 nM nefiracetam. It was concluded that nefiracetam potentiated NMDA currents through interactions with the glycine binding site of the NMDA receptor.
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PMID:Potentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neurons. 1280 78

Proto-oncogene (c-fos, c-jun) and nuclear factor-kappa B (NF-kappaB) expression, as well as DNA synthesis, in aortic and cerebral vascular smooth muscle cells (VSMCs) were upregulated by a decrease in extracellular magnesium ions ([Mg2+]o). Upregulation of these transcriptional factors was inversely proportional to the [Mg2+]o and occurred over the pathophysiologic range of serum Mg2+ found in patients presenting with hypertension, ischemic heart disease, and stroke. Removal of extracellular Ca2+ ([Ca2+]o), use of nifedipine or protein kinase C (PKC) inhibitors prevented the upregulation of the proto-oncogenes and DNA synthesis in VSMCs. These data show that [Mg2+]o may be an important, heretofore, overlooked natural modulator of proto-oncogene and NF-kappaB expression in VSMCs and that Ca2+ and PKC may play critical roles in induction of c-fos and c-jun in VSMCs induced by a decrease in [Mg2+]o. These results point to a role for low serum Mg2+ in potential development of hypertension, atherogenesis, vascular disease, and stroke.
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PMID:Expression of the nuclear factor-kappaB and proto-oncogenes c-fos and c-jun are induced by low extracellular Mg2+ in aortic and cerebral vascular smooth muscle cells: possible links to hypertension, atherogenesis, and stroke. 1294 25

Significant amounts of di(2-ethylhexyl) phthalate (DEHP) leach out into blood stored in DEHP plasticized polyvinyl chloride (PVC) bags resulting in the exposure of recipients of blood transfusion to this compound. The aim of this study was to find out whether DEHP at these low levels has any effect on the activity of membrane Na(+)-K+ ATPase, since a decrease in this enzyme activity has been reported to take place in a number of disorders like neurodegenerative and psychiatric disorders, coronary artery disease and stroke, syndrome-X, tumours etc. DEHP was administered (ip) at a low dose of 750 microg/100 g body weight to rats and the activity of membrane Na(+)-K+ ATPase in liver, brain and RBC was estimated. Histopathology of brain, activity of HMG CoA reductase (a major rate limiting enzyme in the isoprenoid pathway of which digoxin, the physiological inhibitor of Na(+)-K+ ATPase is a product), intracellular concentration of Ca2+ and Mg2+ in RBC (which is altered as a result of inhibition of Na(+)-K+ ATPase) were also studied. (In the light of the observation of increase of intracellular Ca2+ load and intracellular depletion of Mg2+ when Na(+)-K+ ATPase is inhibited). Histopathology of brain revealed areas of degeneration in the rats administered DEHP. There was significant inhibition of membrane Na(+)-K+ ATPase in brain, liver and RBC. Intracellular Ca2+ increased in the RBC while intracellular Mg2+ decreased. However activity of hepatic HMG CoA reductase decreased. Activity of Na(+)-K+ ATPase and HMG CoA reductase, however returned to normal levels within 7 days of stopping administration of DEHP. The inhibition of membrane Na(+)-K+ ATPase activity by DEHP may indicate the possibility of predisposing recipients of transfusion of blood or hemodialysis to the various disorders mentioned above. However since this effect is reversed when DEHP administration is stopped, it may not be a serious problem in the case of a few transfusion; but in patients receiving repeated blood transfusion as in thalassemia patients or patients undergoing hemodialysis, possibility of this risk has to be considered. This inhibition is a direct effect of DEHP or its metabolites, since activity of HMG CoA reductase, (an enzyme which catalyses a major rate limiting step in the isoprenoid pathway by which digoxin, the physiological inhibitor of Na(+)-K+ ATPase is synthesized) showed a decrease.
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PMID:Inhibition of membrane Na(+)-K+ Atpase of the brain, liver and RBC in rats administered di(2-ethyl hexyl) phthalate (DEHP) a plasticizer used in polyvinyl chloride (PVC) blood storage bags. 1524 77

Cerebral ischemia engages multiple terminal pathways involving the loss of ionic homeostasis, and acute and delayed neuronal damage. Several studies have focused on the derangement of energy metabolism and calcium, but not on magnesium. Hypomagnesium or low dietary magnesium intake may increase the risk of stroke and other cardiovascular diseases. The neuroprotective effects of magnesium have been attributed to a variety of effects on pathophysiologic mechanisms during and after cerebral ischemia, such as antagonizing calcium-mediated metabolic processes, inhibition of the N-methyl-D-aspartate (NMDA) receptors and relaxing vascular smooth muscles. Systemically administered magnesium provides beneficial effects in both clinical patients and cerebral ischemic animal models. Magnesium, as one of the therapeutic agents in stroke treatment, has the advantages of being inexpensive, widely available, and causing few side effects. The optimal doses for the treatment of cerebral ischemia both in animal models and in humans have not been defined yet. Thus, we attempted to evaluate the effects of magnesium on experimental cerebral ischemia.
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PMID:Experimental cerebral ischemia and magnesium. 1557 91

Recent epidemiology has linked high consumption of whole grains with reduced risk for diabetes, coronary disease, stroke, and various types of cancer; there is reason to suspect that improved insulin sensitivity is largely responsible for this protection. This phenomenon may be partially explained by the lower glycemic indices of some whole grain food products in comparison to their fiber-depleted analogs. Nonetheless, the fact that whole wheat flour promotes insulin sensitivity relative to white flour--and yet has a near-identical glycemic index--suggests that certain nutrients or phytochemicals in whole wheat, depleted by the refining process, promote preservation of insulin sensitivity. Magnesium is a likely candidate in this regard; magnesium deficiency promotes insulin resistance in rodents and in humans, whereas supplemental magnesium has been found to prevent type 2 diabetes in rodent models of this syndrome, and to improve the insulin sensitivity of elderly or diabetic humans. Magnesium-rich diets as well as above-average serum magnesium are associated with reduced diabetes risk in prospective epidemiology, and with greater insulin sensitivity in cross-sectional studies; moreover, other types of magnesium-rich foods--dairy products, legumes, and nuts--have been linked to decreased diabetes risk in prospective studies. The biochemical role of magnesium in support of insulin function is still poorly understood. In light of evidence that magnesium can function as a mild natural calcium antagonist, it is interesting to note suggestive evidence that increases in intracellular free calcium may compromise the insulin responsiveness of adipocytes and skeletal muscle, and may indeed play a pathogenic role in the insulin resistance syndrome. Thus, it is proposed that some or all of the favorable impact of good magnesium status on insulin function may reflect antagonism of the induction or effects of increased intracellular free calcium. Further research concerning the potential health benefits of long-term magnesium supplementation is clearly warranted. These considerations, however, should not detract from efforts to better inform the public regarding the strong desirability of choosing whole grain products in preference to refined grains.
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PMID:Magnesium may mediate the favorable impact of whole grains on insulin sensitivity by acting as a mild calcium antagonist. 1561 78

Subarachnoid hemorrhage from a ruptured aneurysm is a subset of stroke. The young age (median 55 years) and poor outcome (50% of patients die; 30% of survivors remain dependent) explain why in the population the loss of productive life years from aneurysmal subarachnoid hemorrhage (SAH) is as large as that from brain infarcts, the most common type of stroke. Ischemia plays an important role in the pathophysiological process after SAH. A period of global cerebral ischemia firstly occurs in the acute phase, immediately after rupture of the aneurysm, due to acute vasoconstriction and elevated intracranial pressure, which leads to a drop in perfusion pressure. This is quite distinct from the secondly, delayed cerebral ischemia (DCI), which is focal or multi-focal. DCI usually occurs between 4 and 10 days after the initial bleeding, has a gradual onset and is multi-focal, and is an important cause of death and dependency after SAH. The interval between the bleeding and the onset of ischemia provides an opportunity for preventive treatment. Magnesium is readily available, inexpensive and has a well-established clinical profile in obstetrical and cardiovascular practice. It is beneficial in the treatment of eclampsia, a disease with a pathophysiology comparable to DCI after subarachnoid hemorrhage. Neuroprotective mechanisms of magnesium include inhibition of the release of excitatory amino-acids and blockade of the NMDA-glutamate receptor. Magnesium is also a non-competitive antagonist of voltage dependent calcium channels, has cerebrovascular dilatory activity and is an important co-factor of cellular ATPases, including the Na/K-ATPase. Magnesium can reverse delayed cerebral vasospasm and reduces the extent of acute ischemic cerebral lesions after experimental subarachnoid hemorrhage in rats. In this article we discuss the neuroprotective potency of magnesium in SAH by describing the pathophysiology of ischaemia after SAH and the many ways magnesium may interfere with this.
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PMID:Potentials of magnesium treatment in subarachnoid haemorrhage. 1572 6

Glutamate-mediated damage to oligodendrocytes contributes to mental or physical impairment in periventricular leukomalacia (pre- or perinatal white matter injury leading to cerebral palsy), spinal cord injury, multiple sclerosis and stroke. Unlike neurons, white matter oligodendrocytes reportedly lack NMDA (N-methyl-d-aspartate) receptors. It is believed that glutamate damages oligodendrocytes, especially their precursor cells, by acting on calcium-permeable AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptors alone or by reversing cystine-glutamate exchange and depriving cells of antioxidant protection. Here we show that precursor, immature and mature oligodendrocytes in the white matter of the cerebellum and corpus callosum exhibit NMDA-evoked currents, mediated by receptors that are blocked only weakly by Mg2+ and that may contain NR1, NR2C and NR3 NMDA receptor subunits. NMDA receptors are present in the myelinating processes of oligodendrocytes, where the small intracellular space could lead to a large rise in intracellular ion concentration in response to NMDA receptor activation. Simulating ischaemia led to development of an inward current in oligodendrocytes, which was partly mediated by NMDA receptors. These results point to NMDA receptors of unusual subunit composition as a potential therapeutic target for preventing white matter damage in a variety of diseases.
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PMID:NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. 1637 11

Since the early 1960s it has been known that restoring extracellular Ca2+ following a period of low Ca2+ concentrations paradoxically causes an increase in intracellular Ca2+ levels that can lead to cell death. The mystery of this 'Ca2+ paradox' is made more intriguing by observations that lowering concentrations of extracellular Ca2+ and/or Mg2+ paradoxically enhances the entry of Ca2+ into hippocampal neurons. Until recently, the entry of Ca2+ through NMDA receptors was accepted as the major pathway leading to the excitotoxic, delayed cell death associated with the ischemic periods of stroke. Here, we discuss how several transient receptor potential (TRP) channels are likely to contribute to both the Ca2+ paradox and the delayed death of neurons following an ischemic stroke.
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PMID:Paradox of Ca2+ signaling, cell death and stroke. 1637 99

Compelling evidence supports contributions of glutamate receptor overactivation ('excitotoxicity') to neurodegeneration in both acute conditions, such as stroke, and chronic neurodegenerative conditions, such as amyotrophic lateral sclerosis. However, anti-excitotoxic therapeutic trials, which have generally targeted highly Ca2+ permeable NMDA-type glutamate channels, have to date failed to demonstrate impressive efficacy. Whereas most AMPA type glutamate channels are Ca2+ impermeable, an evolving body of evidence supports the contention that relatively unusual Ca2+ permeable AMPA channels might be crucial contributors to injury in these conditions. These channels are preferentially expressed in discrete neuronal subpopulations, and their numbers appear to be upregulated in amyotrophic lateral sclerosis and stroke. In addition, unlike NMDA channels, Ca2+ permeable AMPA channels are not blocked by Mg2+, but are highly permeable to another potentially harmful endogenous cation, Zn2+. The targeting of these channels might provide efficacious new avenues in the therapy of certain neurological diseases.
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PMID:Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. 1669 62

Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis, and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here, we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors.
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PMID:Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter. 1804 34


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