Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 N-methyl-D-aspartic acid (NMDA) receptor provides a potential target for gene therapy of focal seizure disorders. To test this approach, we cloned a 729-bp NMDA receptor (NMDAR1) cDNA fragment in the antisense orientation into adeno-associated virus (AAV) vectors, where expression was driven by either a tetracycline-off regulatable promoter (AAV-tTAK-NR1A) or a cytomegalovirus (CMV) promoter (AAV-CMV-NR1A). After infection of primary cultured cortical neurons with recombinant AAV-tTAK-NR1A, patch clamp studies found a significant decrease in maximal NMDA-evoked currents, indicative of a decrease in the number of NMDA receptors. Similarly, infusion of AAV-tTAK-NR1A (1 microl) into the rat temporal cortex significantly decreased NMDAR1-like immunoreactivity in layer V pyramidal cells. When AAV-tTAK-NR1A vectors were infused into the seizure-sensitive site of the rat inferior collicular cortex, the seizure sensitivity increased significantly over a period of 4 weeks. However, collicular infusion of AAV-CMV-NR1A vectors caused the opposite effect, a significant decrease in seizure sensitivity. Subsequent collicular coinfusion of vector encoding green fluorescent protein (GFP) driven by the tetracyclineoff promoter (AAV-tTAK-GFP) and vector encoding beta-galactosidase driven by the CMV promoter (AAV-CMV-LacZ) transduced distinct neuronal populations with only partial overlap. Thus, differing transduction ratios of inhibitory interneurons to primary output neurons likely account for the divergent seizure influences. Although AAV vector-derived NMDAR1 antisense can influence NMDA receptor function both in vitro and in vivo, promoter-related tropic differences dramatically alter the physiological outcome of this receptor-based gene therapy.
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PMID:Therapeutic liabilities of in vivo viral vector tropism: adeno-associated virus vectors, NMDAR1 antisense, and focal seizure sensitivity. 1237 91

Hypoxia of the brain may alter further seizure susceptibility in a different way. In this study, we tried to answer the question how episode of convulsion induced by hypoxia (HS) changes further seizure susceptibility, and how N-methyl-D-aspartic acid (NMDA) and AMPA/KA receptor antagonists influence this process. Adult Albino Swiss mice exposed to hypoxia (5% O(2)) developed clonic/tonic convulsions after about 340 s. Mice which underwent 10 s but not 5 s seizures episode subsequently exhibited significantly increased seizure susceptibility to low doses (equal ED(16)) of bicuculline (BCC) and NMDA during a 3-week observation period. No morphological signs of brain tissue damage were seen in light microscope on the third day after a hypoxia-induced seizure (HS). Learning abilities assessed in passive avoidance test as well as spontaneous alternation were not disturbed after an HS episode. Pretreatment with AMPA/KA receptor antagonist NBQX effectively prolonged latency to HS and given immediately after seizure episode also attenuated subsequent convulsive susceptibility rise, however, NMDA receptor antagonist, MK-801, appeared to be ineffective. These results suggest that a seizure episode induced by hypoxia, depending on its duration, may play an epileptogenic role. The AMPA/KA receptor antagonist prolongs the latency to HS, and given after this episode, prevents the long-term epileptogenic effect.
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PMID:The epileptogenic effect of seizures induced by hypoxia: the role of NMDA and AMPA/KA antagonists. 1247 49

Psychosis caused by phencyclidine (PCP) stimulated interest in characterizing rodent behaviors elicited by PCP and its analogues. We have shown that MK-801 antagonizes electrically precipitated seizures (defined as tonic hindlimb extension) and elicits episodes of intense jumping behavior, referred to as "popping," in mice. Moreover, 24 h after stress, MK-801's ability to antagonize electrically precipitated seizures is reduced in outbred NIH Swiss mice. Inbred BALBc mice are more resistant to electrically precipitated seizures than the NIH Swiss strain, and are more sensitive to both MK-801's anticonvulsant effect and ability to elicit popping. In the current experiments, we examined the influence of stress and genetic mouse strain on both MK-801's ability to antagonize electrically precipitated seizures and elicit popping. Stress significantly reduced the threshold voltage for precipitation of seizures in BALBc mice and the anticonvulsant properties of MK-801 in both strains. These data show that factors relevant to schizophrenia and its exacerbation (i.e., acute stress and genetics) influence N-methyl-D-aspartic acid (NMDA) receptor-mediated neurotransmission in intact mice. The BALBc inbred strain of mouse may possess advantages in preclinical screening paradigms designed to assess NMDA receptor agonist interventions for disorders such as schizophrenia. Specifically, stressed BALBc mice showed the greatest behavioral sensitivity to MK-801 with regard to electrically precipitated seizures in the incremental electroconvulsive shock (IECS) paradigm, whereas unstressed BALBc showed the greatest behavioral sensitivity to MK-801 in the "popping" paradigm, relative to BALBc and NIH Swiss mice in the appropriate comparison conditions.
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PMID:Interaction of stress and strain on glutamatergic neurotransmission: relevance to schizophrenia. 1247 54

Hughlings Jackson at the turn of the century defined epilepsy as a disorder originating in a "morbid nutrition" of the neuron. With the advances in modern neurochemistry, it is becoming increasingly clear that a chronic seizure predisposition or a lowering of the brain's discharge threshold can be demarcated by a number of biochemical markers. They include a tendency for an increased release of glutamate with or without GABAergic impairment, (intra)neural tissue alterations in water redistribution/osmolarity or other distortions of the cytoarchitecture, and an elevation of ionic calcium inside the cell. These changes are dominantly shared parameters of the seizure prone brain. Magnetic resonance spectroscopy (MRS) shows that cerebral levels of glutamate + glutamine (Glx) are increased interictally in epileptogenic regions in human partial epilepsy; other findings using this technique suggest damage to (cellular/mitochondrial) membranes, denoted by N-acetyl-aspartic acid (NAA) changes and a decreased energy capability. The merging of previous in vitro and ex vivo findings in neurophysiology and neurochemistry with magnetic resonance spectroscopy technology provides a powerful new methodology to interpret and to obtain clinical insight into the metabolic alterations that underlie an epileptogenic process. In this review some of these basic neurochemical and electrophysiological mechanisms are discussed. In addition, certain adjuncts to established antiepileptic drug therapy are suggested in the hope that over the long term they may help in correcting the primary metabolic deficits.
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PMID:Metabolic parameters of epilepsy: adjuncts to established antiepileptic drug therapy. 1260 9

Evidence exists that some abused solvents have N-methyl-D-aspartic acid (NMDA) antagonist activity, although which of their effects may be related to this mechanism is not well understood. The effects of toluene and 1,1,1-trichloroethane (TCE) on NMDA-induced seizures in mice were studied using three experimental protocols: (a) animals injected i.p. with 120 or 170 mg/kg NMDA and immediately afterwards exposed to solvent vapors or air for 30 min (co-exposure protocol); (b) mice exposed for 30 min to solvent or air, then injected with NMDA and placed in the chamber for a second 30-min exposure (pre-exposure+co-exposure protocol); and (c) mice that inhaled 4000 ppm toluene or air for 30 min twice a day, 6 h apart, for 7 days, and were injected with 120 mg/kg NMDA immediately before a 30-min toluene exposure (repeated exposure protocol). When given acutely, toluene, but not TCE, produced concentration-dependent protection against NMDA-induced seizures. Higher concentrations of toluene were also effective against the lethal effects produced by 170 mg/kg NMDA. Clearer effects were seen when the pre-exposure+co-exposure protocol was followed. Under these conditions the IC(50) for toluene was 739 ppm (653-825) against seizure occurrence and 2127 ppm (1966-2288) against lethality. Repeated exposure to toluene did not result in tolerance to its anticonvulsant effects. These results are consistent with the in vitro effects described for toluene as a noncompetitive NMDA antagonist and as a compound that enhances GABAergic transmission. The lack of protective effects of TCE is not consistent with its in vitro actions.
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PMID:Effects of inhaled toluene and 1,1,1-trichloroethane on seizures and death produced by N-methyl-D-aspartic acid in mice. 1264 92

Seizure disorders present an attractive gene therapy target, particularly because viral vectors such as adeno-associated virus (AAV) and lentivirus can stably transduce neurons. When we targeted the N-methyl-D-aspartic acid (NMDA) excitatory amino acid receptor with an AAV-delivered antisense oligonucleotide, however, the promoter determined whether focal seizure sensitivity was significantly attenuated or facilitated. One potential means to circumvent this liability would be to express an inhibitory neuroactive peptide and constitutively secrete the peptide from the transduced cell. The neuropeptide galanin can modulate seizure activity in vivo, and the laminar protein fibronectin is usually secreted through a constitutive pathway. Initially, inclusion of the fibronectin secretory signal sequence (FIB) in an AAV vector caused significant gene product secretion in vitro. More importantly, the combination of this secretory signal with the coding sequence for the active galanin peptide significantly attenuated in vivo focal seizure sensitivity, even with different promoters, and prevented kainic acid-induced hilar cell death. Thus, neuroactive peptide expression and local secretion provides a new gene therapy platform for the treatment of neurological disorders.
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PMID:Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. 1289 58

The present results refer to the action of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) on seizure phenomena in mice. TXF and CYP at their lowest protective dose in the electroconvulsive threshold test, enhanced the antiseizure efficacy of some antiepileptic drugs. TXF (20 mg/kg) potentiated the protective activity of valproate, diphenylhydantoin and clonazepam, but not that of carbamazepine or phenobarbital, against maximal electroshock-induced convulsions in female mice. CYP (40 mg/kg) enhanced the anticonvulsant action of valproate, carbamazepine, diphenylhydantoin and clonazepam, but not that of phenobarbital, against maximal electroshock in male animals. MIF failed to affect the electroconvulsive threshold or the efficacy of antiepileptic drugs in maximal electroshock. The effect of TXF or CYP upon the electroconvulsive threshold and on the action of antiepileptics was not reversed by sex steroid hormones (estradiol, testosterone, progesterone). However, the TXF-induced elevation of the electroconvulsive threshold was abolished by bicuculline, N-methyl-D-aspartic acid and kainic acid, and partially reversed by aminophylline, strychnine being ineffective in this respect. The action of CYP on the threshold for electroconvulsions was partially reversed by bicuculline and aminophylline. Both glutamatergic agonists and strychnine remained ineffective in this respect. Moreover, the action of TXF or CYP on the activity of antiepileptics was not influenced by strychnine, and reversed to various extents by the remaining convulsants. In contrast to maximal electroshock, none of the three antihormones affected the protective action of antiepileptic drugs against pentylenetetrazol-induced seizures in mice. Neither TXF nor CYP altered the free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs, providing 50% protection against maximal electroshock, did not affect motor performance in mice, and did not result in significant long-term memory deficits. Our data indicate that steroid receptor-mediated events may be indirectly associated with seizure phenomena in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.
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PMID:Influence of sexual hormone antagonists on the anticonvulsant action of conventional antiepileptic drugs against electrically- and pentylenetetrazol-induced seizures in mice. 1465 91

Loreclezole (5 mg/kg) exerted a significant protective action in amygdala-kindled rats, reducing both seizure and afterdischarge durations. The combinations of loreclezole (2.5 mg/kg) with valproate, clonazepam, or carbamazepine (applied at their subprotective doses) also exhibited antiseizure effect in this test. However, only two first combinations occurred to be of pharmacodynamic nature. Among several chemoconvulsants, bicuculline, N-methyl-D-aspartic acid and BAY k-8644 (the opener of L-type calcium channels) reversed the protective activity of loreclezole alone and its combination with valproate. On the other hand, bicuculline, aminophylline and BAY k-8644 inhibited the anticonvulsive action of loreclezole combined with clonazepam. The results support the hypothesis that the protective activity of loreclezole and its combinations with other antiepileptics may involve potentiation of GABAergic neurotransmission and blockade of L-type of calcium channels.
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PMID:Effect of some convulsants on the protective activity of loreclezole and its combinations with valproate or clonazepam in amygdala-kindled rats. 1470 68

In previous studies for the development of new anticonvulsants, we found that N-Cbz-alpha-amino-N-alkylsuccinimides exhibited significant anticonvulsant activities in the Maximal electroshock seizure (MES) and Pentylenetetrazole induced seizure (PTZ) tests, and also their anticonvulsant activities were dependent on the N-alkyl substituents existent in their structures. Based on these estimations, N-Cbz-alpha-amino-N-hydroxysuccinimide and various N-Cbz-alpha-amino-N-alkoxysuccinimides were prepared in order to develop more active anticonvulsants and to examine the effects of N-hydoxy or N-alkoxy groups on their anticonvulsant activities. The (R)- or (S)-N-Cbz-alpha-amino-N-hydroxysuccinimide and N-Cbz-alpha-amino-N-alkoxysuccinimides were prepared from the corresponding (R)- or (S)-N-Cbz-aspartic acid through the known synthetic procedures. Their anticonvulsant activities in the MES and PTZ test were evaluated. All of these compounds except 3a showed significant anticonvulsant activities against the PTZ test, but these compounds were not active in the MES test. The most active compound in the PTZ test was (R)-N-Cbz-alpha-amino-N-benzyloxysuccinimide (ED50=62.5 mg/kg). In addition, the anticonvulsant activities of these compounds were dependent on their N-substited groups. The order of anticonvulsant activity against the PTZ test, as judged from the ED50 values for (R) series was N-benzyloxy > N-hydroxy > N-isopropoxy > N-methoxy > N-ethoxy; for the (S) series N-ethoxy > N-benzyloxy > N-methoxy > N-isopropoxy.
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PMID:Synthesis and anticonvulsant evaluation of N-Cbz-alpha-amino-N-alkoxysuccinimides. 1508 29

Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is characterized by episodes of syncope, seizures or sudden death, in response to physical activity or emotional stress, and affects mainly young children with morphologically normal hearts. We have recently described an autosomal recessive form of the disorder in seven families from a Bedouin tribe in the north of Israel, and mapped the disease-causing gene to chromosome 1p13-1p21. Direct sequencing of the calsequestrin 2 (CASQ2), a candidate gene from within the linkage interval, revealed a negatively charged aspartic acid change to a positively charged histidine at position 307 of the protein. CASQ2 serves as the major calcium reservoir within cardiac myocytes. This mutation occurs in a highly conserved residue of the protein. The implication of the calcium release cascade in this disease, may lead to a better understanding of the pathophysiologic events underlying ventricular tachycardia, and to the use of drugs directly involved in intracellular calcium control for the treatment of the CPVT patients.
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PMID:A missense mutation in CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. 1517 29


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