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

Soman, a potent acetylcholinesterase inhibitor, induces status epilepticus in rats followed by conspicuous neuropathology, most prominent in piriform cortex and the CA3 region of the hippocampus. Cholinergic seizures originate in striatal-nigral pathways and with fast-acting agents (soman) rapidly spread to limbic related areas and finally culminate in a full-blown status epilepticus. This leads to neurochemical changes, some of which may be neuroprotective whereas others may cause brain damage. Pretreatment with lithium sensitizes the brain to cholinergic seizures. Likewise, other agents that increase limbic hyperactivity may sensitize the brain to cholinergic agents. The hyperactivity associated with the seizure state leads to an increase in intracellular calcium, cellular edema and metal delocalization producing an oxidative stress. These changes induce the synthesis of stress-related proteins such as heat shock proteins, metallothioneins and heme oxygenases. We show that soman-induced seizures cause a depletion in tissue glutathione and an increase in tissue 'catalytic' iron, metallothioneins and heme oxygenase-1. The oxidative stress induces the synthesis of stress-related proteins, which are indicators of 'stress' and possibly provide neuroprotection. These findings suggest that delocalization of iron may catalyze Fenton-like reactions, causing progressive cellular damage via free radical products.
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PMID:Soman-induced seizures: limbic activity, oxidative stress and neuroprotective proteins. 1192 Sep 27

Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.
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PMID:Primary and secondary defects of the mitochondrial respiratory chain. 1213 29

Use of novel drug delivery methods could enhance the efficacy and reduce the toxicity of antiepileptic drugs (AEDs). Slow-release oral forms of medication or depot drugs such as skin patches might improve compliance and therefore seizure control. In emergency situations, administration via rectal, nasal or buccal mucosa can deliver the drug more quickly than can oral administration. Slow-release oral forms and rectal forms of AEDs are already approved for use, nasal and buccal administration is currently off-label and skin patches for AEDs are an attractive but currently hypothetical option. Therapies under development may result in the delivery of AEDs directly to the regions of the brain involved in seizures. Experimental protocols are underway to allow continuous infusion of potent excitatory amino acid antagonists into the CSF. In experiments with animal models of epilepsy, AEDs have been delivered successfully to seizure foci in the brain by programmed infusion pumps, acting in response to computerised EEG seizure detection. Inactive prodrugs can be given systemically and activated at the site of the seizure focus by locally released compounds. One such drug under development is DP-VPA (or DP16), which is cleaved to valproic acid (sodium valproate) by phospholipases at the seizure focus. Liposomes and nanoparticles are engineered micro-reservoirs of a drug, with attached antibodies or receptor-specific binding agents designed to target the particles to a specific region of the body. Liposomes in theory could deliver a high concentration of an AED to a seizure focus. Penetration of the blood-brain barrier can be accomplished by linking large particles to iron transferrin or biological toxins that can cross the barrier. In the near future, it is likely that cell transplants that generate neurotransmitters and neuromodulators will accomplish renewable endogenous drug delivery. However, the survival and viability of transplanted cells have yet to be demonstrated in the clinical setting. Gene therapy also may play a role in local drug delivery with the use of adenovirus, adeno-associated virus, herpesvirus or other delivery vectors to induce brain cells to produce local modulatory substances. New delivery systems should significantly improve the therapeutic/toxic ratio of AEDs.
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PMID:Potential new methods for antiepileptic drug delivery. 1215 31

In order to accelerate welfare and nutrition programs for women and children in tribal, hilly, and backward areas of India, the government of India has accepted the National Program of Integrated Services. Delivery of these services is coordinated by the Integrated Child Development Services (ICDS). The package of services for prenatal women include physical and obstetrical exams; serial recording of weight, blood pressure, hemoglobin, and urinalysis; tetanus immunization; iron (60 mg) and folic acid (.5 mg) tablets; food supplements; identification and referral of high-risk mothers; and health education on antenatal care, breast feeding, child rearing, and family planning. Postnatal women received 2 home visits within 10 days of delivery and make 1 visit after 1 month of delivery. These visits cover general health, breast feeding, delivery records, infant health, and birth control measures. Food supplementation continues for nursing mothers. All women 15-44 years of age receive health and nutrition education. Specially organized courses, campaigns, home visits by anganwadi workers, cooking demonstrations, and mass media emphasize simple messages regarding health and nutrition. Areas that are covered include family welfare; antenatal, intranatal, and postnatal care; breast feeding; immunization; prevention of such common communicable diseases as malaria, tuberculosis, and leprosy; weaning and supplementary feeding; improvement of children's nutritional status; balanced diet; food storage, preparation, cooking, and serving; eye and ear care; personal and environmental hygiene; sanitation; management of acute respiratory infections; management of diarrhea; and control and treatment of internal parasites. The mobile food and extension units of the Department of Food are utilized. Pregnant and nursing mothers belonging to families of landless agricultural laborers, of marginal farmers, of the scheduled caste, of the scheduled tribe, and of poorer sections of the community are chosen for this program. Special care is given to pregnant women who: are pregnant for the 1st, 3rd, or 4th time; have gained less than 6 kg; are younger than 18 or older than 35; have had frequent or twin pregnancies; have a history of miscarriage or preterm delivery; are anemic; or have a history of edema, hypertension, or seizure. Personnel, who are monitored, receive training supplemented by reorientation and continuing education.
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PMID:Health and development of mothers through system of ICDS. 1228 36

The quinolone antibiotics have been a major advance for the treatment of various types of infections. These agents have generally good safety profiles, broad-spectrum activity, and favorable pharmacokinetics. In addition, several of these antibiotics are available in both intravenous and oral formulations, which allows for sequential therapy resulting in potential cost savings. However, patients can develop serious central nervous system side effects (seizures) and phototoxicity. In addition, the bioavailability of agents in this class can be reduced by coadministration with cations, such as magnesium, aluminum, calcium, and iron, which may make bioavailability unpredictable in patients. Although older quinolones such as ciprofloxacin were effective as prophylactic agents for biliary procedures and colorectal surgery and for the treatment of intra-abdominal infections, the use of these older quinolones was limited by the development of resistant organisms. In addition, because these agents had poor activity against anaerobes such as Bacteroides fragilis, the agents had to be combined with an antianaerobic agent, such as metronidazole, when anaerobic coverage was required. Recently, a new quinolone, trovafloxacin, has become available. Trovafloxacin has demonstrated increased activity against anaerobes in animal and human studies. However, the clinical profile of trovafloxacin for abdominal infections has not been fully demonstrated, and there is some concern that its activity against aerobic gram-negative bacilli, especially Pseudomonas aeruginosa, may not equal that of ciprofloxacin. Moreover, the safety profile of trovafloxacin is disadvantageous owing to reports of severe hepatic toxicity.
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PMID:The role of quinolones in abdominal surgery. 1259 11

The rat brain was investigated with structural and functional magnetic resonance imaging (MRI) 12 h after the arrest of pilocarpine-induced status epilepticus lasting 4 h. Histopathological data, obtained immediately after MRI analysis, were correlated with the images through careful evaluation of tissue shrinkage. Diffusion-weighted and T2-weighted imaging showed changes throughout the cerebral cortex, hippocampus, amygdala, and medial thalamus. However, only T2-weighted imaging, based on rapid acquisition relaxation-enhanced sequences, revealed in the cortex inhomogeneous hyperintensity that was highest in a band corresponding to layer V. Regional cerebral blood volume (rCBV) maps were generated using T2*-weighted gradient-echo images and an ultrasmall superparamagnetic iron oxide contrast agent. In the cortex, rCBV peaked in superficial and deep bands exhibiting a distribution complementary to the highest T2-weighted intensity. Selective rCBV increase was also documented in the hippocampus and subcortical structures. In tissue sections, alterations indicative of marked edema were found with Nissl staining in areas corresponding to the highest T2-weighted intensity. Degenerating neurons, revealed by FluoroJadeB histochemistry, were instead concentrated in tissue exhibiting hyperperfusion in rCBV maps, such as hippocampal subfields and dentate gyrus, cortical layers II/III and VI, and medial thalamus. The data indicate that:(i) T2-weighted imaging provides a sensitive tool to investigate edematous brain alterations that follow sustained seizures; (ii) rCBV maps reveal regional hyperperfusion; (iii) rCBV peaks in tissue exhibiting marked neurodegeneration, which may not be selectively revealed by structural MRI. The findings provide an interpretation of the brain response to sustained seizures revealed in vivo by different strategies of MRI analysis.
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PMID:Magnetic resonance imaging of changes elicited by status epilepticus in the rat brain: diffusion-weighted and T2-weighted images, regional blood volume maps, and direct correlation with tissue and cell damage. 1259 91

Guanidino compounds of guanidinoethanesulfonic acid, guanidinoacetic acid, guanidinosuccinic acid, N-acetylarginine, beta-guanidinopropionic acid, creatinine, gamma-guanidinobutyric acid, arginine, guanidine, methylguanidine, homoarginine and alpha-guanidinoglutaric acid are present in the mammalian brain. These guanidino compounds except for arginine and guanidine induce seizures and convulsions in rat, rabbit and cat by intracisternal injection. Hirudonine, audonine, alpha-keto-delta-guanidinovaleric acid, N,N'-dibenzoylguanidine and phenylethylguanidine are also convulsants. Levels of creatinine, guanidinoethanesulfonic acid, creatinine, guanidinoacetic acid and methylguanidine in animal brain were changed at pre- and during convulsions induced by pentylentetrazol, amygdala kindling, iron-induced epileptogenesis and so on. These convulsions are thought to be due to depressed functions of serotonergic neurons and accumulated free radicals. Arginine is a substrate of nitric oxide production by nitric oxide synthase. alpha-Guanidinoglutaric acid is a generator of superoxide, hydroxyl radicals and nitric oxide, and induced C6 glial cell death. On the other hand, aminoguanidine is a free radical scavenger. Energy formation by creatine metabolism may inhibit apoptosis induced by pathogenesis. Free radical generation/ reaction and energy generation by guanidino compounds must be important key role in the brain.
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PMID:A role for guanidino compounds in the brain. 1270 10

The behaviour of brain capillary endothelium to the passage of macromolecules in single and repeated seizures conditions and its relationship to the brain trace element concentrations are the main subject of this study. For this purpose, animals were treated with either single or repeated doses of pentylenetetrazole (PTZ). As a marker of blood-brain barrier (B-BB) permeability changes, Evans Blue (EB) dye was used. Seizure activity was observed and seizure patterns and convulsion times were recorded. PTZ treatment induced generalised tonic-clonic seizure in all animals, but seizures were found to be lasting longer in single seizure group than repeated seizures group. Seizures induced by single dose PTZ treatment resulted in bilateral EB leakage in the preoptic area, caudate nucleus, putamen, thalamus, hypothalamus, midbrain, and the superior colliculus. However, repeated PTZ-induced seizures led to EB leakage in the brains of only few number of rats, and it was confined to hypothalamus, caudate nucleus, cerebellum, thalamus, and pons. On the other hand, while the levels of copper (Cu) and iron (Fe) in brain tissue were found to be decreased significantly in the repeated seizures group when compared with the other groups, the levels of zinc (Zn) did not show any differences between groups. These results indicate that the regional B-BB opening markedly differs between single and repeated PTZ-induced seizures group and this difference may be due to PTZ tolerance and changes in cerebral endothelial structure.
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PMID:Changes in the blood-brain barrier permeability and in the brain tissue trace element concentrations after single and repeated pentylenetetrazole-induced seizures in rats. 1277 May 17

Magnetization measurements and variable temperature optical spectroscopy have been used to investigate, within the 4-300 K temperature range, the electronic structure of the reduced high-potential iron protein (HiPIP) from Chromatium vinosum and the model compounds (Cat)(2)[Fe(4)S(4)(SR)(4)], where RS(-) = 2,4,6-triisopropylphenylthiolate (1), 2,6-diphenylphenylthiolate (2), diphenylmethylthiolate (3), 2,4,6-triisopropylbenzylthiolate (4, 4'), 2,4,6-triphenylbenzylthiolate (5, 5'), 2,4,6-tri-tert-butylbenzylthiolate (6), and Cat(+) = (+)NEt(4) (1, 2, 3, 4', 5', 6), (+)PPh(4) (4, 5). The newly synthesized 2(2)(-), 3(2)(-), 5(2)(-), and 6(2)(-) complexes are, as 1(2)(-) and 4(2)(-), excellent models of the reduced HiPIPs: they exhibit the [Fe(4)S(4)](3+/2+) redox couple, because of the presence of bulky ligands which stabilize the [Fe(4)S(4)](3+) oxidized core. Moreover, the presence of SCH(2) groups in 4(2)(-), 5(2)(-), and 6(2)(-), as in the [Fe(4)S(4)] protein cores, makes them good biomimetic models of the HiPIPs. The X-ray structure of 2 is reported: it crystallizes in the orthorhombic space group Pcca with no imposed symmetry and a D(2)(d)()-distorted geometry of the [Fe(4)S(4)](2+) core. Fit of the magnetization data of the reduced HiPIP and of the 1, 2, 3, 4, 5, and 6 compounds within the exchange and double exchange theoretical framework leads to exchange coupling parameters J = 261-397 cm(-)(1). A firm determination of the double exchange parameters B or, equivalently, the transfer integrals beta = 5B could not be achieved that way. The obtained |B| values remain however high, attesting thus to the strength of the spin-dependent electronic delocalization which is responsible for lowest lying electronic states being characterized by delocalized mixed-valence pairs of maximum spin (9)/(2). Electronic properties of these systems are then accounted for by the population of a diamagnetic ground level and excited paramagnetic triplet and quintet levels, which are respectively J and 3J above the ground level. Optical studies of 1, 2, 4', 5', and 6 but also of (NEt(4))(2)[Fe(4)S(4)(SCH(2)C(6)H(5))(4)] and the isomorph (NEt(4))(2)[Fe(4)S(4)(S-t-Bu)(4)] and (NEt(4))(2)[Fe(4)Se(4)(S-t-Bu)(4)] compounds reveal two absorption bands in the near infrared region, at 705-760 nm and 1270-1430 nm, which appear to be characteristic of valence-delocalized and ferromagnetically coupled [Fe(2)X(2)](+) (X = S, Se) units. The |B| and |beta| values can be directly determined from the location at 10|B| of the low-energy band, and are respectively of 699-787 and 3497-3937 cm(-)(1). Both absorption bands are also present in the 77 K spectrum of the reduced HiPIP, at 700 and 1040 nm (Cerdonio, M.; Wang, R.-H.; Rawlings, J.; Gray, H. B. J. Am. Chem. Soc. 1974, 96, 6534-6535). The blue shift of the low-energy band is attributed to the inequivalent environments of the Fe sites in the protein, rather than to an increase of |beta| when going from the models to the HiPIP. The small differences observed in known geometries of [Fe(4)S(4)](2+) clusters, especially in the Fe-Fe distances, cannot probably lead to drastic changes in the direct Fe-Fe interactions (parameter beta) responsible for the delocalization phenomenon. These differences are however magnetostructurally significant as shown by the 261-397 cm(-)(1) range spanned by J. The cluster's geometry, hence the efficiency of the Femicro(3)-S-Fe superexchange pathways, is proposed to be controlled by the more or less tight fit of the cluster within the cavity provided by its environment.
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PMID:Investigation of the reduced high-potential iron-sulfur protein from chromatium vinosum and relevant model compounds: a unified picture of the electronic structure of [Fe(4)S(4)](2+) systems through magnetic and optical studies. 1455 35

The pigmentary type of orthochromatic leukodystrophy (van Bogaert-Nyssen disease) is a hardly known neurological disorder usually with late onset that is very difficult to diagnose in vivo. Neuropathologically, the disorder features noninflammatory demyelination and the presence of pigmented macrophages and astrocytes that may contain iron. Clinically, van Bogaert-Nyssen disease can lead to death within a few years and is characterized by dementia, psychiatric abnormalities, epileptic seizures, spastic pareses, and occasionally extrapyramidal motor symptoms. This report presents a typical case and an overview of the literature. Furthermore, galactocerebroside could be documented in remaining macrophages and astrocytes by immunohistochemistry. This possibly indicates a dysfunction in sphingolipid breakdown and could relate the pigmented form of orthochromatic leukodystrophy to the genetically defined globoid cell leukodystrophy (Krabbe's disease). Thus, the rather heterogeneous pool of orthochromatic leukodystrophies could be further narrowed.
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PMID:[Pigmented form of orthochromatic leukodystrophy]. 1464 15


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