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

Evidence from animal stroke models suggests that the proximate cause of neuronal degeneration after ischemia is massive release of glutamate and activation of NMDA receptors. However, in the physiologic presence of oxygen and glucose in the rat hippocampal slice preparation, the neurotoxicity of glutamate, as measured by inhibition of protein synthesis, requires high concentrations and is not prevented by glutamate receptor antagonists. Thus, the NMDA receptor-mediated neurotoxic effects of extracellular glutamate accumulation during ischemia might depend on additional factors, such as neuronal depolarization. In the experiments reported here, slices were exposed to glutamate in a medium intended to mimic the ionic conditions found during ischemia, high potassium (128 mM) and low sodium (26 mM). This depolarizing medium itself inhibited protein synthesis in a manner which was partially mediated by NMDA receptor activation, since it was significantly reversed by the noncompetitive NMDA antagonist, MK-801. Furthermore, the effect of glutamate under depolarizing conditions was also significantly decreased by MK-801, suggesting that glutamate was acting at NMDA receptors. Thus, depolarization appears to enhance the sensitivity of neurons to toxic NMDA receptor activation by glutamate. Under conditions that mimic ischemia, hypoxia plus hypoglycemia, a similar protective effect of NMDA receptor antagonists was observed. Depolarization and ischemia both appeared to attenuate the neurotoxicity of non-NMDA receptor agonists. It appears that under conditions of normal glucose and oxygen, high concentrations of bath applied glutamate inhibit protein synthesis at sites other than the NMDA receptor. However, when the Na+ gradient is decreased, as occurs during ischemia, glutamate's NMDA effects predominate. These findings suggest that ionic shifts may play a central role in permitting NMDA receptor-mediated ischemic neuronal damage.
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PMID:Enhancement of NMDA receptor-mediated neurotoxicity in the hippocampal slice by depolarization and ischemia. 165 99

1. Splanchnic haemodynamic changes were studied in seven healthy subjects during hypoglycaemia induced by the intravenous infusion of insulin. Superior mesenteric artery blood flow and cardiac output were examined noninvasively by a Doppler ultrasound technique. 2. Blood glucose concentration fell from 4.5 (0.14) mmol/l basally to 1.5 (0.09) mmol/l [mean (SEM), P less than 0.003] at the hypoglycaemic reaction ('R') and recovered to baseline by 'R' + 60 min. There was an associated rise in plasma glucagon, adrenaline and noradrenaline levels. 3. Superior mesenteric artery blood flow rose at 'R' from a basal value of 532 (38) ml/min to a peak of 803 (73) ml/min at 'R' + 10 min [mean (SEM), P less than 0.005] and remained significantly elevated until 'R' + 40 min. Resistance in this vessel fell by 33% at 'R' + 10 min (P less than 0.005) and remained significantly low until 'R' + 40 min. 4. Cardiac output rose by 33% at 'R' (P less than 0.004) and returned to normal by 'R' + 20 min. This was associated with a 24% rise in pulse rate (P less than 0.03), but no change in stroke volume or mean arterial pressure. Total peripheral resistance fell by 21% at 'R' (P less than 0.005) and had returned to normal by 'R' + 20 min. 5. The sustained rise in splanchnic blood flow during hypoglycaemic recovery may be of homoeostatic importance by providing metabolic fuel to the liver for gluconeogenesis.
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PMID:Splanchnic haemodynamic changes during acute hypoglycaemia in man. 165 99

Recent data suggest that brain damage in ischemia, hypoglycemia, and several other brain diseases is caused by excitotoxic mechanisms which are triggered by presynaptic release of glutamate and related excitatory amino acids, and which involve an abnormal postsynaptic influx of calcium into cells containing a high density of glutamate receptors. This contention is supported by results demonstrating reduction of infarct size in focal ischemia due to middle cerebral artery (MCA) occlusion, and amelioration of neuronal necrosis in hypoglycemic coma, by antagonist which block the NMDA type of glutamate receptor. These results underscore the pathogenetic role of calcium influx into energy-compromised cells since the NMDA receptor-linked ion channel has a high conductance to calcium. The issue has been clouded by the inability of NMDA antagonists to ameliorate brain damage due to cardiac arrest, or to forebrain ischemia in rats and gerbils. In these conditions, however, an AMPA receptor blocker (NBQX) has been found efficacious. These results demonstrate that the pathophysiology of ischemic lesions is different in the cardiac arrest type of ischemia and in lesions due to MCA occlusion, and demand an explanation of the differences in therapeutic response. Tentatively, the cardiac arrest type of ischemia is so dense that multiple calcium conductances are activated in the energy-deprived tissue, explaining why any drug which acts on only one of them (such as an NMDA antagonist) cannot prevent cellular calcium overload. Furthermore the ultimate brain damage, which is often conspicuously delayed, may be secondary to upregulation of synaptic efficacy, causing increased calcium cycling and calcium-related damage. In this situation, an AMPA receptor blocker may be efficacious because it blocks "fast" excitation and Na+ influx, an "upstream" event which causes "downstream" calcium influx via multiple pathways. In the perifocal ("penumbra") zone of a stroke lesion, the situation is different since depolarisation is initially moderate and/or intermittent. Furthermore, since ATP is still produced (albeit at a reduced rate) the problem is one of a disturbed pump/leak relationship. Then, blockade of a major calcium-carrying channel by NMDA receptor blockers, or of the trigger to depolarisation by an AMPA receptor antagonist, may improve the pump/leak relationship and carry cells in the penumbra over a critical period.
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PMID:Neurocytotoxicity: pharmacological implications. 168 4

The experiments were designed to test the possibility that calcium influx into neurons via voltage sensitive calcium channels (VSCCs) contribute to brain damage in two conditions in which any amelioration of neuronal necrosis may be assumed not to occur through an improvement of blood flow, viz., hypoglycemic coma and brief transient ischemia. Hypoglycemic coma is thought to lead to neuronal necrosis by release of glutamate and cellular influx of calcium during the insult, while damage due to brief transient ischemia may, at least in part, result from increased calcium cycling across cell membranes in the postinsult period. The insults were delivered to anesthetized rats, and the localization and density of neuronal necrosis were evaluated by histopathology following 1 week of recovery. One dihydropyridine calcium antagonist (isradipine), given in doses which have been reported to ameliorate ischemic damage due to stroke, failed to reduce damage incurred by 30 min of hypoglycemic coma, or 15 min of transient forebrain ischemia. Provided that it can be assumed that isradipine in the doses employed reduced calcium influx via VSCCs, the results support the notion that calcium influx through VSCCs plays only a minor pathogenetic role in global/forebrain ischemia or in hypoglycemia, and they suggest that the effect of blockers of VSCCs in stroke, if any, is due to both blockade of VSCCs and increase in blood flow.
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PMID:The effect of a dihydropyridine calcium antagonist (isradipine) on selective neuronal necrosis. 183 Aug 97

Non-insulin-dependent diabetes mellitus (NIDDM) is a common disorder occurring in 3-6% of adults in most western populations. In the United States, 29% of patients with diabetes take insulin; of these, 76% have NIDDM. Insulin therapy is usually required at some time in NIDDM. Insulin therapy improves the abnormalities of NIDDM (reduced beta-cell function, increased hepatic glucose production, reduced peripheral glucose disposal, lipid abnormalities). Insulin and sulfonylurea agents have comparable effects on mild forms of NIDDM, but for more severe forms, insulin is usually superior. Combination insulin-sulfonylurea treatment may improve the response to sulfonylureas, although long-term well-controlled trials have not been conducted. Short-term insulin treatment may restore response to sulfonylureas. Other promising treatments (human proinsulin, nasal insulin, somatostatin) have not shown any advantage over conventional insulin therapy. Insulin causes hypoglycemia and peripheral hyperinsulinemia. The hazards of hyperinsulinemia, e.g., weight gain and hypoglycemia, have been overstated, and questions about its atherogenic effects remain to be resolved. The effect of glycemic control on macro- and microvascular complications has not been established; however, maintaining fasting blood glucose levels of less than 6.7 mM may protect against progression of retinopathy, neuropathy, and nephropathy and reduce the severity of ischemic stroke. Dosage algorithms generally use intermediate- or long-acting insulin to control basal glycemia, with regular insulin added before meals if needed to control postprandial glycemia. Effective therapy depends on the patient being informed, cooperative, and willing to self-monitor blood glucose. Insulin treatment intermittency increases the risk for immune complications (resistance and allergy). Overall, patients with NIDDM can benefit from insulin therapy.
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PMID:Treatment of NIDDM with insulin agonists or substitutes. 198 Apr 53

There is evidence that free radical activity may be important in the development of endotoxemia. Dimethyl sulfoxide is a hydroxyl radical scavenger that readily penetrates cell membranes. Using the conscious, instrumented rat this study tests the ability of dimethyl sulfoxide to modify the course of endotoxemia by evaluating cardiovascular, metabolic, and tissue injury parameters for 4 hr after the toxic insult. Treatment with dimethyl sulfoxide (6.5 g/kg; i.p.) evoked significant decreases in cardiac output, stroke volume, and central venous pressure and increases in heart rate, systemic vascular resistance, mean aortic pressure, respiration rate, and concentrations of blood glucose and plasma lactate. Following endotoxin (40 mg/kg, i.v. LD90- 24 hr), dimethyl sulfoxide pretreatment blocked the early hypotensive episode but all other cardiovascular and respiratory responses to endotoxin were essentially unaltered. The pH, PO2, PCO2, and hematocrit were the same for both treated and untreated groups; however, dimethyl sulfoxide prevented the endotoxin-induced hypoglycemia and significantly attenuated the hyperlacticemia at 4 hr. The severe hemorrhagic intestinal pathology characteristic of this model of endotoxemia was not present in the dimethyl-sulfoxide-treated group. From these results we conclude that dimethyl sulfoxide caused significant cardiovascular alterations conducive to impaired systemic blood flow. However, when administered prior to endotoxin, dimethyl sulfoxide induced significant beneficial modifications in the course of endotoxemia despite few improvements in cardiovascular function. The data indicate that the hydroxyl radical may be a mediator of tissue injury in this model of endotoxemia.
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PMID:Dimethyl sulfoxide antagonizes hypotensive, metabolic, and pathologic responses induced by endotoxin. 204 8

We used neonatal piglets to determine the influence of plasma glucose concentration on cerebral energy metabolism during and immediately after partial ischemia. We assessed cerebral metabolism using in vivo phosphorus-31 magnetic resonance spectroscopy. Arterial plasma glucose concentration was increased in four piglets by systemic infusions of dextrose in water for comparison with infusions of saline in four controls or decreased in eight piglets by fasting for 24-48 hours for comparison with four fed piglets. Plasma glucose concentration showed a significant linear correlation with intracellular pH (r = -0.7, p less than 0.05). Piglets that developed hypoglycemia during partial ischemia had a smaller reduction in intracellular pH and a larger increase in inorganic phosphate content than piglets that were normoglycemic or hyperglycemic during ischemia. Similar differences persisted during the first 5 minutes of postischemic reperfusion. Subsequently, the cerebral concentrations of phosphorylated compounds returned to normal in all piglets. Our results demonstrate that 1) arterial plasma glucose concentration influences cerebral energy metabolism and intracellular pH during ischemia, 2) neonatal piglets can develop profound brain acidosis, and 3) brain acidosis during ischemia does not influence the restoration of cerebral phosphorylated compounds to control levels during the first 90 minutes after ischemia.
Stroke 1990 Mar
PMID:Effect of plasma glucose concentration on cerebral metabolism during partial ischemia in neonatal piglets. 210 36

The empiric administration of 50% dextrose to all patients presenting to the ED with altered mental status is a standard of care predicated on the assumption that glucose administration is harmless to nonhypoglycemic patients. Considerable evidence now disputes this assumption. Glucose administration before complete cerebral ischemia in experimental animals worsens neurologic and histologic outcome. Administration of glucose during severe incomplete ischemia has a similar detrimental effect. The translation of these experimental findings into clinical practice has been slow, perhaps hindered by the frequent use of rodent models and large bolus doses of glucose. However, evidence is now provided by primate and human studies and by experimental designs using clinically relevant doses of glucose. These clinical and experimental findings in conjunction with the wide availability of a rapid bedside screen for hypoglycemia provide the rationale for an alteration in the standard of care. The empiric administration of glucose should be avoided in patients at risk of cerebral ischemia, such as those with acute stroke, impending cardiac arrest, or severe hypotension or receiving CPR. A bedside fingerstick blood glucose estimation should be performed immediately on all patients presenting with altered mental status. The administration of 50% dextrose should be reserved for those patients in whom hypoglycemia is demonstrated; this practice will uphold Hippocrates' most basic principle of clinical medicine, "The physician must...do no harm."
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PMID:50% dextrose: antidote or toxin? 212 May 1

Excitatory amino acid (EAA)-mediated synaptic transmission is the most prevalent excitatory system within the mammalian brain. Activation of EAA receptors has been postulated to contribute to neuronal cell death in stroke, epilepsy, hypoglycemia, and Huntington's disease. Kynurenic acid is an endogenous substance that inhibits EAA receptors and may therefore influence important physiologic and pathologic processes. The release of intracerebrally synthesized kynurenic acid into the extracellular fluid (ECF), where it may act at EAA receptors, has not been established in vivo. We studied the synthesis and release of kynurenic acid in the rat striatum using intracerebral microdialysis coupled with high performance liquid chromatography and fluorescence detection. The basal ECF concentration of kynurenic acid in the rat corpus striatum was 17.1 +/- 1.1 nM. Peripheral administration of the immediate biosynthetic precursor of kynurenic acid, L-kynurenine, resulted in marked dose-dependent increases in striatal ECF concentrations of kynurenic acid, peaking at 2-2.5 hr. The highest dose of L-kynurenine (100 mg/kg), administered peripherally, resulted in a 108-fold increase in plasma kynurenic acid levels and a 37-fold increase in cerebral ECF levels. Peripheral administration of kynurenic acid, at a dose that caused plasma levels to increase 430-fold, resulted in only 4-fold increases in striatal ECF concentrations. The precursor responsiveness of striatal ECF kynurenic acid to peripherally infused L-kynurenine was blocked by the central application (via the dialysis probe) of aminooxyacetic acid, an inhibitor of the immediate synthetic enzyme for kynurenic acid, kynurenine aminotransferase. Administration of L-tryptophan was less effective than L-kynurenine in increasing ECF kynurenic acid concentrations and did so at a considerably later time interval (6 hr).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors. 216 40

The empiric administration of 50% dextrose to all patients presenting to the ED with altered mental status is a standard of care predicated on the assumption that glucose administration is harmless to non-hypoglycemic patients. Considerable evidence now disputes this assumption. Glucose administration before complete cerebral ischemia in experimental animals worsens neurologic and histologic outcome. Administration of glucose during severe incomplete ischemia has a similar detrimental effect. The translation of these experimental findings into clinical practice has been slow, perhaps hindered by the frequent use of rodent models and large bolus doses of glucose. However, evidence is now provided by primate and human studies and by experimental designs using clinically relevant doses of glucose. These clinical and experimental findings in conjunction with the wide availability of a rapid bedside screen for hypoglycemia provide the rationale for an alteration in the standard of care. The empiric administration of glucose should be avoided in patients at risk for cerebral ischemia, such as those with acute stroke, impending cardiac arrest, or severe hypotension or receiving CPR. A bedside fingerstick blood glucose estimation should be performed immediately on all patients presenting with altered mental status. The administration of 50% dextrose should be reserved for those patients in whom hypoglycemia is demonstrated; this practice will uphold Hippocrates' most basic principle of clinical medicine, "The physician must ... do no harm."
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PMID:50% dextrose: antidote or toxin? 218 38


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