Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epilepsy is a chronic disease, often with an onset during childhood and characterized by spontaneous and recurrent seizures. It concerns 0.5-1% of children under 16 years of age. A classification proposed by the International League Against Epilepsy (ILEA) in 2001 takes into account recent genetic factors involved in epilepsy and attenuates the sharp demarcation between generalized and partial seizures. This classification tends to define whether imaging is indicated or not. Imaging is useless in simple cases of fits associated with hyperthermia and in benign idiopathic epilepsy. It is debated if it is a first episode of epilepsy without a particular context and no neurological signs. In all other cases of epilepsy in children, imaging is indicated. In descending order of frequency the possible causes include malformations (as abnormal gyral development and phakomatoses), hypoxic-ischemic lesions, non-accidental injuries, infections, metabolic diseases and tumors. Being much more sensitive than computed tomography (CT), magnetic resonance imaging (MRI) is the technique of choice to identify an underlying cause in symptomatic epilepsy. Clinical data are mandatory in order to direct a proper MRI investigation. The recently developed diffusion-weighted sequence is particularly useful in the acute phase of certain events such as hypoxia-ischemia, trauma and metabolic disease. CT scan is used in emergency situations and also as a complement to MRI for example to identify calcified lesions. In this way, imaging contributes to establish the nature and define the extension of epileptogenic lesions, thereby guiding therapeutic management. MRI also allows follow-up of the consequences of repeated seizures (such as mesial temporal sclerosis and selective neuronal necrosis) on the cerebral parenchyma and plays a role in the establishment of a prognosis.
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PMID:[Imaging in paediatric epilepsy]. 1573 36

A novel delta-receptor selective compound, ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2, 5-dimethylpiperazin-1-ylmethyl)benzoic acid], was evaluated for activity on infarct size in a rat model of acute myocardial infarction. ARD-353 was characterized as having delta receptor selectivity using radioligand binding and had no apparent selectivity between delta receptor subtypes as determined by [(3)H] cyclic [D-Pen(2),D-Pen(5)]enkephalin (delta(1)) and [(3)H]Deltorphin II (delta(2)) competition binding. ARD-353 also showed selective delta receptor agonist activity in mouse-isolated vas deferens. There was no evidence of any seizure-like convulsions when ARD-353 was administered to mice either i.v. or p.o., implying minimal penetration of the blood-brain barrier. ARD-353 decreased infarct size in a left anterior descending coronary artery (LAD) occlusion model of myocardial infarction. In animals pretreated with ARD-353 (i.v.) and then subjected to 30 min of LAD occlusion followed by 90 min of reperfusion, infarct size was reduced in a dose-dependent manner compared with vehicle-treated controls. The effects of ARD-353 on infarct size were blocked by the delta(1)-opioid selective antagonist 7-benzylidenenaltrexone, indicating a significant role for the delta(1)-opioid receptor in the cardioprotective mechanism of ARD-353. ARD-353 (0.3 mg/kg i.v.) produced significant protection when administered 5 min and 12 and 48 h before ischemic insult or when given immediately after the ischemic insult (at the start of reperfusion). Given the lack of central nervous system effects and beneficial efficacy in the rat model of myocardial ischemia, it is felt that ARD-353 is the first nonpeptide delta-receptor agonist with true potential for clinical use before surgically induced ischemia or in an emergency setting.
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PMID:ARD-353 [4-((2R,5S)-4-(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl)-2,5-dimethylpiperazin-1-ylmethyl)benzoic acid], a novel nonpeptide delta receptor agonist, reduces myocardial infarct size without central effects. 1618 52

Ischemia/reperfusion is a frequently encountered phenomenon in organisms. Prolonged ischemia followed then by reperfusion results in severe oxidative injury in tissues and organs; however, some species can tolerate such events better than others. In nature, arousal from hibernation and resurfacing from diving causes animals to experience classic ischemia/reperfusion and, somehow, these animals cope well with the potential oxidative stress. It has been documented that during these physiological ischemia/reperfusion events, the activities of several antioxidant enzymes and the levels of some small-molecular-weight antioxidants become elevated. For example, the potent small-molecular-weight antioxidant melatonin often attains especially high levels during these physiological ischemia/reperfusion events including during arousal from hibernation or in the newborns during delivery. Highly elevated melatonin production during these physiological ischemia/reperfusion episodes exhibits several features. First, this high melatonin production is transient and fits well with the time schedule of the physiological ischemia/reperfusion period; therefore, it is not related to the normal endogenous melatonin rhythm. Yet, this transient peak protects the animals from destructive oxidative processes that occur during these transition periods. Second, these high levels of melatonin seem to derive from several organs since pinealectomy does not totally reduce circulating levels of this agent. Third, high melatonin production present at arousal from hibernation or in the newborns at birth does not appear to be controlled by light, i.e., it occurs both during the day and at night, and the amplitudes of elevated melatonin levels are equivalent at these times. The significance of these findings is discussed herein. Based on currently available data, we hypothesize that melatonin plays an important role in the physiological ischemia/reperfusion, i.e., as a member of antioxidant defense system, to protect against the potential oxidative injury induced by the physiological ischemia/reperfusion.
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PMID:Physiological ischemia/reperfusion phenomena and their relation to endogenous melatonin production: a hypothesis. 1621 28

The dopaminergic drugs, bromocriptine, cabergoline, dihydroergocryptine, pergolide and ropinirole were injected subcutaneously (s.c.) at the dose of 0.1, 0.5 and 1 mg/kg/day for 7 days into male rats of the Sprague-Dawley strain. The drug pre-treatment reverted amnesia induced in rats by hypobaric hypopxia and tested in active and passive avoidance tasks. A restoration of memory retention, as assessed in a step-through passive avoidance task, was found in animals with a 2-month brain occlusive ischemia and exposed to dopaminergic drugs for 7 days. For behavioral effects in both active and passive avoidance tests in both experimental models, the rank of relative potency was ropirinole>bromocriptine=cabergoline>pergolide>dihydroergocryptine. Spontaneous ambulation of animals with brain occlusive ischemia was increased by the higher doses of drugs. All dopaminergic drugs reduced kainate mortality rate. The rank of relative potency for this effect was ropirinole=bromocriptine=cabergoline>pergolide=dihydroergocryptine. However, no change was found in other seizure parameters (latency to first convulsion and total number of convulsions) after drug treatment. A biochemical analysis of glutathione redox index (glutathione reduced/glutathione oxidized ratio) in discrete brain areas revealed that exposure to dopaminergic drugs increased this parameter in frontal cortex, striatum and hippocampus of animals subject to hypobaric hypoxia and brain occlusive ischemia. For this effect, the relative potency rank was ropirinole>bromocriptine=cabergoline>>pergolide=dihydroergocryptine. These behavioral and biochemical findings suggest that dopaminergic drugs may counteract either behavioral or biochemical changes induced by experimental models of brain injury. This activity was found after protective activity (as found in animals pre-treated with these drugs and exposed to hypobaric hypoxia) or reversal of brain injury (as found in animals treated after 2-month occlusive brain ischemia). Their neuroprotective activity probably involves the reduction/oxidation balance of the glutathione system in the brain.
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PMID:Dopaminergic drugs may counteract behavioral and biochemical changes induced by models of brain injury. 1624 19

Monosialoganglioside (GM1) is a glycosphingolipid that protects against some neurological conditions, such as seizures and ischemia. Glutaric acidemia type I (GA-I) is an inherited disease characterized by striatal degeneration, seizures, and accumulation of glutaric acid (GA). In this study, we show that GA inhibits Na+,K+-ATPase activity and increases oxidative damage markers (total protein carbonylation and thiobarbituric acid-reactive substances-TBARS) production in striatal homogenates from rats in vitro and ex vivo. It is also shown that GM1 (50 mg/kg, i.p., twice) protects against GA-induced (4 micromol/striatum) seizures, protein carbonylation, TBARS increase, and inhibition of Na+,K+-ATPase activity ex vivo. Convulsive episodes induced by GA strongly correlated with Na+,K+-ATPase activity inhibition in the injected striatum but not with oxidative stress marker measures. Muscimol (46 pmol/striatum), but not MK-801 (3 nmol/striatum) and DNQX (8 nmol/striatum) prevented GA-induced convulsions, increase of TBARS and protein carbonylation and inhibition of Na+,K+-ATPase activity. The protection of GM1 and muscimol against GA-induced seizures strongly correlated with Na+,K+-ATPase activity maintenance ex vivo. In addition, GM1 (50-200 microM) protected against Na+,K+-ATPase inhibition induced by GA (6 mM) but not against oxidative damage in vitro. GM1 also decreased pentylenetetrazole (PTZ)-induced (1.8 micromol/striatum) seizures, Na+,K+-ATPase inhibition, and increase of TBARS and protein carbonyl in the striatum. These data suggest that Na+,K+-ATPase and GABA(A) receptor-mediated mechanisms may play important roles in GA-induced seizures and in their prevention by GM1.
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PMID:GM1 ganglioside prevents seizures, Na+,K+-ATPase activity inhibition and oxidative stress induced by glutaric acid and pentylenetetrazole. 1651 83

Ischemia models are indispensable for the evaluation of measures to be clinically applied to brain trauma or stroke patients. Slice models provide good control over experimental parameters and allow for comparative examinations of human and animal brain tissue. Experimental tissue, however, may be altered by anaesthesia, preparatory technique, and, in the case of human tissue, by underlying diseases. These influences on tissue behaviour under ischemia were examined electrophysiologically. Native rat tissue slices were prepared either immediately after decapitation (n = 13), during short ether/barbiturate narcosis (n = 18), or after two hours of inhalation anaesthesia (n = 12) imitating clinical narcosis. Tissue from rats in which generalized amygdala-kindled seizures had been triggered by electric stimulation (n = 10) was prepared according to the decapitation protocol, while human tissue (n = 10) was obtained during epilepsy or tumour surgery. Electrophysiological data (latency and amplitude of anoxic depolarization, recovery of evoked potentials) were recorded during ischemia simulation. Neither details of preparation or anaesthesia nor a history of epileptic fits were associated with significant changes of electrophysiological reactions under ischemia. Human tissue showed a significantly higher ability to uphold transmembrane ion gradients under ischemia. The ability of brain tissue to withstand ischemia is obviously species dependent. For the transfer of experimental results into clinical use it is important that interspecies differences alone can bring about a significant change of tissue behaviour.
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PMID:Electrophysiology in ischemic neocortical brain slices: species differences vs. influences of anaesthesia and preparation. 1662 36

Normal pregnancy is associated with significant changes in the neuronal and vascular control mechanisms of blood pressure (BP). Preeclampsia (PE) is a major complication of pregnancy characterized by proteinuria, and increased vascular resistance and BP. If untreated, PE leads to eclampsia with serious seizures and severe hypertension. However, the neurovascular mechanisms of hypertension in pregnancy and PE are unclear. Studies in animal models of hypertension in pregnancy suggest that inadequate cytotrophoblast invasion of uterine spiral arteries causes reduction in uteroplacental perfusion pressure leading to placental ischemia/hypoxia. Placental ischemia may promote the release of biologically active factors such as cytokines and reactive oxygen species. These circulating factors may increase the vascular permeability, cross the blood-brain barrier, and affect the sympathetic tone and the neuronal control mechanisms of BP. Placental factors could also cause endothelial cell dysfunction and inhibit nitric oxide (NO)-cyclic guanosine monophosphate (cGMP), prostacyclin (PGI(2))-cyclic adenosine monophosphate (cAMP), and hyperpolarizing factor vascular relaxation pathways. Additionally, placental factors may induce endothelium-derived contracting factors such as endothelin, thromboxane and angiotensin II, which stimulate Ca(2+)-dependent vascular smooth muscle (VSM) contraction or increase protein kinase C activity and enhance myofilament sensitivity to intracellular free calcium concentration ([Ca(2+)](i)). The increased sympathetic tone combined with systemic decrease in endothelium-dependent vascular relaxation and enhanced VSM contraction may contribute to the increased vascular resistance and BP associated with PE. The hypertensive state in severe PE may weaken the blood-brain barrier and precipitate convulsions and cerebral hemorrhage. Careful monitoring of maternal neuronal, endothelial, and VSM function during pregnancy should circumvent the life-threatening neurovascular complications of PE-eclampsia.
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PMID:Neurovascular mechanisms of hypertension in pregnancy. 1671 96

Glutamate is the main excitatory neurotransmitter in central nervous system (CNS) and NMDA receptors are one of the major classes of ionotropic glutamate receptors. NMDA receptors have been known to play critical roles in normal CNS activities, as well as in many pathological conditions, including both acute and chronic diseases. The discovery of glycine as a coagonist of NMDA receptors has led to intensive research of glycine/NMDA antagonists as potential CNS drugs. The robust efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5), in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA-1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. However, through SAR studies, compounds such as ACEA-1416 (10) have been identified with improved properties, such as higher in vivo potency and site for potential metabolism. Therefore these compounds should be able to overcome some of the liabilities of ACEA-1021 and potentially could be developed as neuroprotectants. Based on the preclinical and clinical studies of glycine/NMDA antagonists, as well as the clinical experiences with t-PA, initiation of treatment within a short time window after the onset of stroke could be critical for the success of these antagonists in clinical trials. This can be accomplished by implementing the procedure developed for t-PA clinical trials, with modification based on the safety profile of glycine/NMDA antagonists, for future clinical trial to administer the drug as soon as possible after stroke onset. In addition, glycine/NMDA antagonists also have other potential therapeutic applications, such as for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions.
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PMID:Glycine/NMDA receptor antagonists as potential CNS therapeutic agents: ACEA-1021 and related compounds. 1671 7

Acute seizures following brain injury have been associated with a worsening of patient outcome, but they are often undiagnosed and untreated when they occur without motor convulsions. Here, we sought to compare the antiseizure profile of ethosuximide (EXM; 125-312.5 mg/kg i.v.) and gabapentin (GBP; 0.3-50 mg/kg. i.v.) in a rat model of nonconvulsive seizures (NCS) induced by brain ischemia. Seizures were detected by continuous electroencephalographic monitoring for 24 h following permanent middle cerebral artery occlusion (MCAo). Both "preseizure" and "postseizure" treatment effects were evaluated. Control rats experienced a 91% incidence of NCS (averaging 10-11 NCS/rat), which was significantly reduced following preseizure treatment (delivered 20 min post-MCAo) with either EXM (ED(50) = 161 mg/kg) or GBP (ED(50) = 10.5 mg/kg). In contrast to preseizure treatment effects, only GBP reduced NCS when given after the first seizure event. A further, albeit nonsignificant, 20% reduction in NCS incidence was measured when given in combination postseizure. Drug treatment also reduced infarct volume, which was positively correlated to the number of NCS events (r = 0.475; P < 0.001). EXM and GBP treatment of cultured neurons exposed to neurotoxic or ischemic insults showed no neuroprotective effects, suggesting that in vivo neuroprotection can be attributed to anti-seizure effects. We conclude that EXM and GBP significantly attenuate NCS in a dose-related manner and may help to improve patient outcome from brain ischemia-induced seizure activity.
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PMID:Evaluation of gabapentin and ethosuximide for treatment of acute nonconvulsive seizures following ischemic brain injury in rats. 1672 90

Asphyxia i a condition caused by lack of oxygen in tissues and organs. The basic pathogenic mechanisms of asphyxia are: 1)hypoxemia, 2) ischemia. The effects of perinatal asphyxia on the brain of a neonatal baby are critical in development of hypoxic-ischemic encephalopathy. The diagnosis of hypoxic-ischemic encephalopathy is based on clinical data including course of pregnancy and delivery (Apgar score) and especially on the neurological status of the newborn (consciousness, tonus, convulsions, reflexes, vegetative functions, etc.) and it can be confirmed by biochemical analysis and neurological examinations. The aim of this paper is to determine the importance of prenatal and perinatal risk factors for hypoxic-ischemic encephalopathy, as well as their effects on the development of neurological complications and further neurological problems. The research included 148 newborn infants born in the period from January 1, 1996 to January 1, 1999, with gestational age of 27 to 42 weeks, with hypoxic ischemic lesions of the central nervosus system. The control group included 58 children of the same age and the same gestation, with generalized hypotonia ("floppy infant") but without any signs of hypoxic ischemic lesions of the central nervous system. In the group of examined newborn infants with hypoxic ischemic lesions, from 149 children 1 (0.67%) died, 87 (53.89%) had normal findings, whereas the handicap was established in 61 (40.94%). Perinatal asphyxia affects the fetus and newborn infants not by individual factors, but with at least three or four associated factors. The disorders caused by asphyxia are in inverse proportion to the duration and intensity of hypoxic insults and the gestational age of the newborn.
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PMID:Monitoring of neurological parameters in newborns with hypoxic-ischemic encephalopathy. 1763 93


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