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)

The neuronal ceroidlipofuscinoses (NCL) are a group of neurodegenerative disorders and are the most common lysosomal storage diseases of infancy and childhood. Juvenile NCL is caused by CLN3 mutation, producing retinal degeneration, uncontrollable seizures, cognitive and motor decline, and early death before the age of 30 years. To study the pathogenetic mechanisms of the disease, Cln3 knock-in mice (Cln3(Deltaex7/8)) have been generated, which reproduce the 1.02-kb deletion in the CLN3 gene observed in more than 85% of juvenile NCL patients. To characterize the impact of the common Cln3 mutation on development of autofluorescent storage material, gliosis, glucose metabolism, oxidative stress, and transmitter receptors during postnatal brain maturation, brain tissue of Cln3(Deltaex7/8) mice at the ages of 3, 4, 5, 6, 9, and 19 months was subjected to immunocytochemistry to label gliotic markers and nitric oxide synthases; photometric assays to assess enzyme activities of glycolysis and antioxidative defense systems; and level of reactive nitrogen species as well as quantitative receptor autoradiography to detect select cholinergic, glutamatergic, and GABAergic receptor subtypes. The developmental increase in cerebral cortical autofluorescent lipofuscin-like deposition is accompanied by a significant astro- and microgliosis, increased activities of lactate dehydrogenase and phosphofructokinase, decreased level of glutathione peroxidase, enhanced amount of reactive nitrogen species, and lowered binding levels of N-methyl-D-aspartate- and M1-muscarinic acetylcholine receptors in select brain regions but hardly in GABA(A) receptor sites compared with wild-type mice. Detailed elucidation of the sequence of pathological events during postnatal development highlights new potential strategies for symptomatic treatment of the disease.
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PMID:Developmental impairments of select neurotransmitter systems in brains of Cln3(Deltaex7/8) knock-in mice, an animal model of juvenile neuronal ceroid lipofuscinosis. 1826 13

The vast majority of primary brain tumors derive from glial cells and are collectively called gliomas. While, they share some genetic mutations with other cancers, they do present with a unique biology and have developed adaptations to meet specific biological needs. Notably, glioma growth is physically restricted by the skull, and, unless normal brain cells are destroyed, tumors cannot expand. To overcome this challenge, glioma cells release glutamate which causes excitotoxic death to surrounding neurons, thereby vacating room for tumor expansion. The released glutamate also explains peritumoral seizures which are a common symptom early in the disease. Glutamate release occurs via system X(c), a cystine-glutamate exchanger that releases glutamate in exchange for cystine being imported for the synthesis of the cellular antioxidant GSH. It protects tumor cells from endogenously produced reactive oxygen and nitrogen species but also endows tumors with an enhanced resistance to radiation- and chemotherapy. Pre-clinical data demonstrates that pharmacological inhibition of system X(c) causes GSH depletion which slows tumor growth and curtails tumor invasion in vivo. An Food and Drug Administration approved drug candidate is currently being introduced into clinical trials for the treatment of malignant glioma.
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PMID:A role for glutamate in growth and invasion of primary brain tumors. 1828 16

A series of new substituted 1,2,4-thiadiazoles were synthesized by appropriate route and screened for anticonvulsant, neurotoxic and sedative-hypnotic activity. The structures of the synthesized compounds were confirmed by IR spectroscopy, (13)C NMR and elemental (nitrogen and sulphur) analysis. After i.p. injection of the compounds to mice or rate at doses of 30, 100, and 300 mg/kg, body weights were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models after 0.5 and 4 h. Rotorod method and phenobarbitone-induced hypnosis potentiation study were employed to examine neurotoxicity and sedative-hypnotic activity, respectively. All the compounds except 4g showed protection against MES screen after 0.5 h. Compounds 3a-c, 4a-c were active at 100 mg/kg dose i.p., whereas remaining compounds showed activity at 300 mg/kg. All 14 compounds except 3g showed neurotoxicity at 100 and 300 mg/kg after 0.5 h. Compounds 3b and 4b showed NT after 4 h. Two compounds 3b and 4g showed significant (p<0.05) percentage increase in sleeping time i.e. 67% and 59%, respectively. It may be concluded that the synthesized compounds were potent against MES-induced seizures than ScPTZ induced and showed low potency as sedative-hypnotic agent which is advantageous.
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PMID:Synthesis and anticonvulsant activity of some substituted 1,2,4-thiadiazoles. 1867 18

Recent investigations have elucidated some of the diverse roles played by reactive oxygen and nitrogen species in events that lead to oxygen toxicity and defend against it. The focus of this review is on toxic and protective mechanisms in hyperoxia that have been investigated in our laboratories, with an emphasis on interactions of nitric oxide (NO) with other endogenous chemical species and with different physiological systems. It is now emerging from these studies that the anatomical localization of NO release, which depends, in part, on whether the oxygen exposure is normobaric or hyperbaric, strongly influences whether toxicity emerges and what form it takes, for example, acute lung injury, central nervous system excitation, or both. Spatial effects also contribute to differences in the susceptibility of different cells in organs at risk from hyperoxia, especially in the brain and lungs. As additional nodes are identified in this interactive network of toxic and protective responses, future advances may open up the possibility of novel pharmacological interventions to extend both the time and partial pressures of oxygen exposures that can be safely tolerated. The implications of a better understanding of the mechanisms by which NO contributes to central nervous system oxygen toxicity may include new insights into the pathogenesis of seizures of diverse etiologies. Likewise, improved knowledge of NO-based mechanisms of pulmonary oxygen toxicity may enhance our understanding of other types of lung injury associated with oxidative or nitrosative stress.
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PMID:Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity. 1884 74

Drug profiling, extraction of physical and/or chemical profiles from abused drug samples, is useful for inferring and characterizing links between samples originating from the same and different seizures, and supports drug crime investigations. We describe an evaluation method for linking methamphetamine (MA) seizures using stable carbon and nitrogen isotopic compositions concurrently with gas chromatographic impurity profiling, which is one of the major methods of drug profiling. Several sets of MA seized in Japan, whose investigative information indicated linkages, were analyzed. The impurity profile of each set of seizures was quite similar and hierarchical cluster analysis showed a sample classification that was relatively consistent with the investigative information. The stable carbon and nitrogen isotopic compositions of the MA seizures varied between -29.40 and -24.90 (delta(13)C) and -2.29 and 5.94 (delta(15)N), respectively. In the delta(13)C-delta(15)N graph, MA seizures were classified into seven groups, probably reflecting different origins. The size of the cluster in the isotopic-composition graph was determined by pooled standard deviations (s(p)), the pooled estimates of measurement uncertainty. The sizes of the clusters were less than 6s(p) and the linkages between the MA seizures from the isotopic compositions were consistent with the impurity profiling and investigative information. The results showed that complementary use of stable-isotopic compositions with impurity profiling provides useful information for evaluating the links between seizures.
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PMID:Evaluation method for linking methamphetamine seizures using stable carbon and nitrogen isotopic compositions: a complementary study with impurity profiling. 1898 Feb 65

Formation of reactive oxygen and nitrogen species is a precipitating event in an array of neuropathological conditions. In response to excessive reactive oxygen species (ROS) levels, transcriptionally dependent mechanisms drive the up-regulation of ROS scavenging proteins which, in turn, limit the extent of brain damage. Here, we employed a transgenic approach in which cAMP-response element binding protein (CREB)-mediated transcription is repressed (via A-CREB) to examine the contribution of the CREB/cAMP response element pathway to neuroprotection and its potential role in limiting ROS toxicity. Using the pilocarpine-evoked repetitive seizure model, we detected a marked enhancement of cell death in A-CREB transgenic mice. Paralleling this, there was a dramatic increase in tyrosine nitration (a marker of reactive species formation) in A-CREB transgenic mice. In addition, inducible expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha was diminished in A-CREB transgenic mice, as was activity of complex I of the mitochondrial electron transport chain. Finally, the neuroprotective effect of brain-derived neurotrophic factor (BDNF) against ROS-mediated cell death was abrogated by disruption of CREB-mediated transcription. Together, these data both extend our understanding of CREB functionality and provide in vivo validation for a model in which CREB functions as a pivotal upstream integrator of neuroprotective signaling against ROS-mediated cell death.
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PMID:The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death. 1914 Oct 71

Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p<0.01) increases in biomarkers of ROS (F2-isoprostanes, F2-IsoPs; and F4-neuroprostanes, F4-NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p<0.01) reductions in dendritic lengths and spine density. When rats were pretreated with the antioxidants N-tert-butyl-alpha-phenylnitrone (PBN, 200 mg/kg, i.p.), or vitamin E (100 mg/kg, i.p./day for 3 days), or memantine (18 mg/kg, i.p.), significant attenuations in DFP-induced increases in F2-IsoPs, F4-NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.
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PMID:Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist. 1961 94

Here, we report sudden, unexplained neurological collapse in 14 young people while bathing with hot water associated with the use of liquefied petroleum gas (LPG)-based water heaters (gas geysers) in ill-ventilated bathrooms. None of the patients reported any circumstantial evidence of seizures or prior epilepsy. One patient developed cortical blindness and demonstrated posterior leucoencephalopathy on imaging studies. The remaining patients made rapid and excellent recovery without any residual neurological sequelae. In these cases, the results of all routine investigations, i.e., serum chemistry, brain imaging (computed tomography in 2 and magnetic resonance imaging in 10) and electroencephalography were normal. The clinical clustering of these cases in winter months with similar presentations of reversible encephalopathy probably indicates an inhalational toxin exposure. Therefore, we postulate a hypothesis that harmful emissions consisting of carbon monoxide (CO), hydrocarbon gases (HC) and nitrogen oxides (NOx), produced by incomplete combustion of LPG might be responsible for the cellular injury and subsequent transient neurological deficits. Physicians should be aware of this entity in order to avoid misdiagnosis of this condition as seizures, and a public awareness should also be created regarding the proper use of these devices.
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PMID:Unexplained neurological events during bathing in young people: Possible association with the use of gas geysers. 1989 47

Our previous work demonstrated the marked decrease of mitochondrial complex I activity in the cerebral cortex of immature rats during the acute phase of seizures induced by bilateral intracerebroventricular infusion of dl-homocysteic acid (600 nmol/side) and at short time following these seizures. The present study demonstrates that the marked decrease ( approximately 60%) of mitochondrial complex I activity persists during the long periods of survival, up to 5 weeks, following these seizures, i.e. periods corresponding to the development of spontaneous seizures (epileptogenesis) in this model of seizures. The decrease was selective for complex I and it was not associated with changes in the size of the assembled complex I or with changes in mitochondrial content of complex I. Inhibition of complex I was accompanied by a parallel, up to 5 weeks lasting significant increase (15-30%) of three independent mitochondrial markers of oxidative damage, 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyls. This suggests that oxidative modification may be most likely responsible for the sustained deficiency of complex I activity although potential role of other factors cannot be excluded. Pronounced inhibition of complex I was not accompanied by impaired ATP production, apparently due to excess capacity of complex I documented by energy thresholds. The decrease of complex I activity was substantially reduced by treatment with selected free radical scavengers. It could also be attenuated by pretreatment with (S)-3,4-DCPG (an agonist for subtype 8 of group III metabotropic glutamate receptors) which had also a partial antiepileptogenic effect. It can be assumed that the persisting inhibition of complex I may lead to the enhanced production of reactive oxygen and/or nitrogen species, contributing not only to neuronal injury demonstrated in this model of seizures but also to epileptogenesis.
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PMID:Sustained deficiency of mitochondrial complex I activity during long periods of survival after seizures induced in immature rats by homocysteic acid. 1993 36

A series of 4-aryl substituted semicarbazones of pyridyl carbaldehyde and pyridyl methyl ketone were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. The structure of synthesized compounds were confirmed by IR spectroscopy, PMR spectroscopy and nitrogen estimation. All the compounds were evaluated for anticonvulsant activity and neurotoxicity. Anticonvulsant activity was determined after intraperitoneal (i.p.) administration to mice by maximal electroshock (MES) and subcutaneous metrazol (ScMet) induced seizure methods and minimal motor impairment was determined by rotorod test. Majority of compounds exhibited significant anticonvulsant activity after intraperitoneal administration. The results obtained showed that 85.7 % of the compounds afforded protection in the MES test and 64.2 % of the total compounds afforded protection in ScPTZ test. Some of them also showed good activity after oral administration. In this study (Methyl-4- pyridyl) ketone -N(4)- (p- chloro phenyl) substituted semicarbazone emerged as most active derivative showing activity at 100 mg/kg in both the test with prolonged duration of action. In the present study semicarbazones of pyridyl containing carbonyl compounds emerges as the lead molecule, showing broad spectrum of activity with low neurotoxicity and prolong duration of action on oral administration. Thus these may be utilized for the future development of novel anticonvulsants with broad spectrum of anticonvulsant activity.
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PMID:Anticonvulsant and neurotoxicity evaluation of some N(4) phenyl substituted pyridyl semicarbazones. 2002 62


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