Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paradox of aerobic life, or the 'Oxygen Paradox', is that higher eukaryotic aerobic organisms cannot exist without oxygen, yet oxygen is inherently dangerous to their existence. This 'dark side' of oxygen relates directly to the fact that each oxygen atom has one unpaired electron in its outer valence shell, and molecular oxygen has two unpaired electrons. Thus atomic oxygen is a free radical and molecular oxygen is a (free) bi-radical. Concerted tetravalent reduction of oxygen by the mitochondrial electron-transport chain, to produce water, is considered to be a relatively safe process; however, the univalent reduction of oxygen generates reactive intermediates. The reductive environment of the cellular milieu provides ample opportunities for oxygen to undergo unscheduled univalent reduction. Thus the superoxide anion radical, hydrogen peroxide and the extremely reactive hydroxyl radical are common products of life in an aerobic environment, and these agents appear to be responsible for oxygen toxicity. To survive in such an unfriendly oxygen environment, living organisms generate--or garner from their surroundings--a variety of water- and lipid-soluble antioxidant compounds. Additionally, a series of antioxidant enzymes, whose role is to intercept and inactivate reactive oxygen intermediates, is synthesized by all known aerobic organisms. Although extremely important, the antioxidant enzymes and compounds are not completely effective in preventing oxidative damage. To deal with the damage that does still occur, a series of damage removal/repair enzymes, for proteins, lipids and DNA, is synthesized. Finally, since oxidative stress levels may vary from time to time, organisms are able to adapt to such fluctuating stresses by inducing the synthesis of antioxidant enzymes and damage removal/repair enzymes. In a perfect world the story would end here; unfortunately, biology is seldom so precise. The reality appears to be that, despite the valiant antioxidant and repair mechanisms described above, oxidative damage remains an inescapable outcome of aerobic existence. In recent years oxidative stress has been implicated in a wide variety of degenerative processes, diseases and syndromes, including the following: mutagenesis, cell transformation and cancer; atherosclerosis, arteriosclerosis, heart attacks, strokes and ischaemia/reperfusion injury; chronic inflammatory diseases, such as rheumatoid arthritis, lupus erythematosus and psoriatic arthritis; acute inflammatory problems, such as wound healing; photo-oxidative stresses to the eye, such as cataract; central-nervous-system disorders, such as certain forms of familial amyotrophic lateral sclerosis, certain glutathione peroxidase-linked adolescent seizures, Parkinson's disease and Alzheimer's dementia; and a wide variety of age-related disorders, perhaps even including factors underlying the aging process itself. Some of these oxidation-linked diseases or disorders can be exacerbated, perhaps even initiated, by numerous environmental pro-oxidants and/or pro-oxidant drugs and foods. Alternatively, compounds found in certain foods may be able to significantly bolster biological resistance against oxidants. Currently, great interest centres on the possible protective value of a wide variety of plant-derived antioxidant compounds, particularly those from fruits and vegetables.
 ...
PMID:Oxidative stress: the paradox of aerobic life. 866 Mar 87

Proton magnetic resonance spectra include signals from N-acetylaspartate, creatine + phosphocreatine, and choline-containing compounds. Abnormalities in these signals can be used in the assessment of patients with intractable epilepsy. In particular, they provide a means of identifying metabolic abnormalities within the temporal lobes, detecting bilateral and diffuse pathology, and aiding lateralization of the seizure focus. The pathology demonstrated on MRS can also be related to cognitive dysfunction.
 ...
PMID:N-acetylaspartate and epilepsy. 875 Mar 36

The effects of NMDA receptor antagonists on the convulsant action of the administration of 4-aminopyridine in the rat lateral cerebral ventricle (i.c.v. injection) and motor cerebral cortex (i.cx. injection) were studied. 4-Aminopyridine administration in both regions induced various preconvulsive symptoms, such as salivation, tremors, chewing and rearing, followed by continuous clonic convulsions and, only after i.c.v. injection, running fits and generalized tonic convulsions. This behavioral pattern appeared 5-9 min after administration of 4-aminopyridine and persisted for 100-150 min. 4-Aminopyridine also generated epileptiform electroencephalographic (EEG) discharges characterized by isolated spikes, poly-spikes and spike-wave complexes, which began some seconds after administration of the drug and were present for more than 2 h. The NMDA receptor antagonists (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), (+/-)-2-amino-7-phosphono-heptanoic acid (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) clearly protected against some of the behavioral alterations induced by i.c.v. 4-aminopyridine, particularly the tonic convulsions, but were less effective against those produced by i.cx. 4-aminopyridine. These antagonists also delayed the appearance of EEG epileptiform discharges, reduced its amplitude, frequency and duration, and blocked their propagation to other cortical regions after i.cx. 4-aminopyridine. These results, together with previous data showing that 4-aminopyridine stimulates the release of glutamate in vivo, suggest that an excessive glutamatergic neurotransmission involving NMDA receptors is implicated in 4-amino-pyridine-induced seizures.
 ...
PMID:Protection by NMDA receptor antagonists against seizures induced by intracerebral administration of 4-aminopyridine. 881 36

Proton magnetic resonance spectroscopy (MRS) has demonstrated reduction of N-acetylaspartate (NAA) in the epileptogenic temporal lobe. However, the correlation of NAA reduction with cerebral metabolic abnormalities is unknown in temporal lobe epilepsy (TLE). Proton MRS and 18F-fluorodeoxyglucose positron emission tomography (FDG/PET) were used to study 12 unilateral TLE patients with medically intractable seizures and 26 age-matched healthy volunteers. The epileptogenic temporal lobe of each patient was determined by both electroencephalography and FDG/PET. The NAA/choline-plus-creatine (NAA/(Cho+Cr)) ratio correlated significantly with the interictal glucose metabolism (r = 0.54, P < 0.01) in 12 TLE patients. The mean NAA/(Cho+Cr) ratio in the epileptogenic temporal lobe was significantly less than that in the contralateral side (P < 0.01), and less than that in normal control temporal lobes (P < 0.0001). These results suggest that quantitative MRS abnormalities reflect underlying metabolic pathology in TLE.
 ...
PMID:Temporal lobe epilepsy: correlation of proton magnetic resonance spectroscopy and 18F-fluorodeoxyglucose positron emission tomography. 897 28

Recent studies have demonstrated that substituted N-benzyl 2-acetamidoacetamides provide significant protection against maximal electroshock (MES)-induced seizures in mice and rats. In this study, we investigated whether the 2-acetamido moiety was necessary for anticonvulsant activity. Ten derivatives of the known anticonvulsant, N-benzyl 2-acetamido-2-phenyl-acetamide were prepared in which the 2-acetamido group was replaced by hydrogen, methyl, oxygen, and halogen substituents. Evaluation of these compounds in the MES-induced seizure test demonstrated that both the hydroxy and the methexy compounds provided full protection against MES-induced seizures in mice given ip at 100 mg/kg. Moreover, evaluation of the individual stereoisomers for the hydroxy compound showed that the principal activity resided in the (R)-isomer. These findings demonstrated that the 2-acetamido substituent is important but not obligatory for the prevention of MES-induced seizures. Further supporting evidence was provided by comparing the pharmacological activities of N-benzyl 2,3-dimethoxypropionamide with N-benzyl 2-acetamido-3-methoxypropionamide. The ED50 value for the former in the MES test was 30 mg/kg (i.p.), which compared favorably with phenobarbital (ED50 = 22 mg/kg), but the ED50 value for N-benzyl 2-acetamido-3-methoxypropionamide was 8.3 mg/kg.
 ...
PMID:The anticonvulsant activities of functionalized N-benzyl 2-acetamidoacetamides. The importance of the 2-acetamido substituent. 902 75

We prospectively studied eight patients with complex partial seizures, using single-voxel proton magnetic resonance spectroscopy (MRS). Control data from 12 healthy volunteers were obtained with the same MRS protocol. The ratios between the peak areas of N-acetylaspartate, creatine and phosphocreatine (Cr), and choline-containing compounds (Cho) were analyzed. The results showed statistically significant lower N-acetylaspartate:Cr, N-acetylaspartate:Cho, and N-acetylaspartate: Cho + Cr ratios, and a higher Cho:Cr ratio in the mesial temporal lobes of the patient group than in healthy controls. Because N-acetylaspartate is located in the neurons and Cho and Cr in the glial cells, these observations represent the underlying neuronal loss and reactive astrocytosis in the epileptogenic foci. MRS can detect abnormal metabolic changes in most complex partial seizure patients with normal electroencephalography and magnetic resonance images. MRS can also identify bitemporal abnormalities which are a common feature in patients with complex partial seizures. Proton MRS could not confirm the specific location of seizure foci. Further investigation with quantitative spectral analysis and correlation with surgical outcome is needed to improve the contribution of MRS to the diagnosis and localization of seizure foci.
 ...
PMID:Proton magnetic resonance spectroscopy in patients with complex partial seizures. 929 Feb 68

We examined the pharmacological profiles of generalized absence seizures in three mouse models: two mutant strains with spontaneous absence seizures, lethargic and stargazer, and ddY mice (GHB model) in which absence seizures were induced by administering gamma-butyrolactone (GBL), a prodrug of gamma-hydroxybutyric acid (GHB). A typical antiabsence drug, ethosuximide (200 mg/kg), attenuated absence seizure behavior, spike and wave and paroxysmal discharges (SWDs and PDs) in each model. P-[3-Aminopropyl]-P-diethoxymethylphosphinic acid (CGP 35348), a selective gamma-aminobutyric acid (GABA)B antagonist (200 mg/kg), suppressed absence seizure behavior, SWDs and PDs at least as effectively as ethosuximide (200 mg/kg) in lethargic and GHB model mice. P-[3-Aminopropyl]-P-cyclohexylmethylphosphinic acid (CGP 46381) was more effective than CGP 35348 and ethosuximide in these models. Although the antiabsence effect of CGP 46381 was as strong as that of ethosuximide (200 mg/kg) in stargazer mice, CGP 35348 (200-400 mg/kg) was weaker than ethosuximide. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine hydrogen maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) antagonist (0.5 mg/kg), had no effects on SWDs and PDs in lethargic or GHB model mice. Although MK-801 (0.5 mg/kg) suppressed SWDs significantly in stargazer mice, irregular electroencephalographic patterns were observed. These results suggest that GABAB receptors play a significant role in the pathogenesis of generalized absence seizures in these models, although the mechanism involved in stargazer mice differ from that in the other two.
 ...
PMID:Pharmacological profiles of generalized absence seizures in lethargic, stargazer and gamma-hydroxybutyrate-treated model mice. 929 89

Surgery is a safe and effective treatment for patients with temporal lobe epilepsy (TLE) who do not respond adequately to anticonvulsant medication and in whom the seizure generator can be identified and safely removed. Proton MR spectroscopic imaging (MRSI) can image and quantify neuronal damage in patients with TLE based on reduced signals from N-acetylaspartate (NAA), a compound localized exclusively in neurons. We performed proton MRSI in patients with TLE before and after surgical treatment to determine whether NAA or other resonance intensities changed in the temporal lobes of patients with TLE after surgery, and whether these changes correlated with surgical outcome. N-acetylaspartate resonance intensity relative to creatine (NAA/Cr) was abnormally low preoperatively in at least one temporal lobe in all 14 patients examined. It was low ipsilaterally in the patients who became seizure free and bilaterally in those who did not. Postoperatively, it increased to the normal range on the side of surgery in all patients who became seizure free. In the one patient who became seizure free and who had low NAA/Cr in both temporal lobes before surgery, NAA/Cr values in the contralateral, unoperated temporal lobe also increased to the normal range. In contrast, NAA relative intensity ratios did not change in those patients who continued to have seizures after surgery. The creatine resonance intensity (Cr) in the temporal lobes was high, relative to the brainstem, in seven patients preoperatively. After surgery, the Cr remained high in two patients, both of whom continued to have seizures. We conclude that NAA (and Cr) abnormalities in TLE do not result solely from neuronal loss and gliosis but can be reversible after postsurgical control of seizures. This implies that the NAA and Cr abnormalities in patients with TLE, at least in part, are dynamic markers of both local and remote physiologic dysfunction associated with ongoing seizures.
 ...
PMID:Normalization of neuronal metabolic dysfunction after surgery for temporal lobe epilepsy. Evidence from proton MR spectroscopic imaging. 940 40

Dimethylsulfoxide (DMSO) formed a ternary complex when mixed with a Zn-3, 5-diisopropylsalicylate complex of unknown structure. The structure of this new ternary complex was characterized in an initial effort to understand the nature of this compound. Since the original complex is known to have anticonvulsant activity, the new ternary complex was also examined for anticonvulsant activity. The original complex was examined for inhibition of the polymorphonuclear leukocyte (PMNL) respiratory burst in an effort to mechanistically account for zinc complex mediated anticonvulsant activity. Dissolving the structurally unknown complex in DMSO gave crystals of a characterizable complex with an empirical formula C30H46O8S2Zn. Crystallographic data: P 1, Z = 2, a = 8.06(1), b = 12.452(2), c = 17.951(2) A, alpha = 74.42(l), beta = 77.07(1), gamma = 89.50(1) degree. The structure was refined to R = 0.03, RW = 0.04 for 3815 independent reflections with I > 2 sigma(I). This complex is mononuclear, with two 3,5-diisopropylsalicylate ligands and two bonded DMSO ligands, Zn(II)(3,5-DIPS)2(DMSO)2, Zn(II) is coordinate covalently bonded to four O atoms in a strongly distorted tetrahedral arrangement. Each DMSO ligates via its sulfoxide O atom while each 3,5-diisopropylsalicylate ligand is monodentate The non-ligating carbonyl O atom of each 3,5-DIPS is free except for an intramolecular hydrogen bond from the hydroxy group of the same ligand. Both 3,5-DIPS acid and Zn(II)(3,5-DIPS)2(DMSO)2 were examined for anticonvulsant activity in the Maximal Electroshock (MES) and Metrazol (MET) models of seizures and found to prevent both types of seizures. The Zn complex was qualitatively and quantitatively more effective than treatment with the free ligand. The influence of a Zn 3,5-DIPS complex and of the ligand 3,5-DIPS on PMNL oxidative metabolism was also studied to help understand the mechanism of anticonvulsant activity of these compounds. A dose-related and significant decrease in chemiluminescent (CL) response to opsonized Zymosan was observed, and the Zn complex was significantly more effective than the free ligand. It is concluded that mononuclear Zn complexes have anticonvulsant activity in Grand Mal and Petit Mal models of seizure possibly due to inhibition of the synthesis of superoxide or down-regulation of Nitric Oxide Synthase in activated phagocytic cells of the central nervous system.
 ...
PMID:Crystal structure of 180 degree K of bis-3, 5-diisopropylsalicylatobisdimethylsulfoxidozinc(II) and the inhibition of seizures and polymorphonuclear leukocyte chemiluminescence. 966 72

The effects of 14 different 1,4-benzodiazepines on amygdaloid-kindled seizures and their chemical structure-related anticonvulsive actions were studied. The prophylactic effects of 1, 4-benzodiazepines on amygdaloid-kindled seizures were also examined. Male Wistar strain rats were used in this study. Rats were anesthetized with pentobarbital sodium (35 mg/kg i.p.) and bipolar electrodes were implanted into the right amygdala. The stimulating parameters were 1 ms pulse duration, 60 Hz frequency and a 1 s duration at an intensity just sufficient to induce afterdischarge (AD). All the 1,4-benzodiazepines depressed both seizure stage and AD duration of amygdaloid-kindled seizures. Of the 1, 4-benzodiazepines, prazepam, flutoprazepam and flurazepam with a long alkyl chain at position 1 were less effective than the drugs having a hydrogen or methyl group at the same position. Nitrazepam, nimetazepam, flunitrazepam and clonazepam which have a nitro group at position 7 showed more potent antiepileptic activity than the drugs with a chloro group. Certain 1,4-benzodiazepines caused inhibition of the development of amygdaloid-kindled seizures. The existence of a hydrogen or methyl group at position 1 and a nitro group at position 7 is important for exhibiting potent anticonvulsant activity in amygdaloid-kindled seizures. Introduction of an oxygen group at position 2 is also necessary for high activity. 1,4-benzodiazepines had not only therapeutic but also prophylactic effects on amygdaloid-kindled seizures.
 ...
PMID:Anticonvulsant properties of 1,4-benzodiazepine derivatives in amygdaloid-kindled seizures and their chemical structure-related anticonvulsant action. 974 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>