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)

PSD-93, a molecular adaptive protein, binds to and clusters the N-methyl-D-aspartate (NMDA) receptor and assembles a specific set of signaling proteins (for example neuronal nitric oxide synthase, nNOS) around the NMDA receptor at synapses in the central nervous system. This suggests that PSD-93 might mediate many NMDA receptor-dependent physiological and pathophysiological functions. We report here that PSD-93 colocalizes and interacts with the NMDA receptor and neuronal nitric oxide synthase in cultured cortical neurons. Targeted disruption of PSD-93 gene significantly prevented NMDA receptor-nitric oxide signaling-dependent neurotoxicity triggered via platelet-activating factor (PAF) receptor activation. In addition, the deficiency of PSD-93 markedly attenuated platelet-activating factor-induced increase in cyclic guanosine 3',5'-monophosphate (cGMP) and prevented platelet-activating factor-promoted formation of NMDA receptor-neuronal nitric oxide synthase complex. These findings indicate that PSD-93 is involved in the NMDA receptor--nitric oxide-mediated pathological processing of neuronal damage triggered via platelet--activating factor receptor activation. Since platelet-activating factor is a potent neuronal injury mediator during the development of brain trauma, seizures, and ischemia, the present work suggests that PSD-93 might contribute to molecular mechanisms of neuronal damage in these brain disorders.
 ...
PMID:Targeted disruption of PSD-93 gene reduces platelet-activating factor-induced neurotoxicity in cultured cortical neurons. 1529 32

Recent evidence indicates that sildenafil may exert some central effects through enhancement of nitric oxide (NO)-mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NO-mediated mechanisms. This study was performed to examine whether sildenafil influences the threshold of clonic and/or generalized tonic seizures through modulation of nitric oxide (NO)-cGMP pathway. The effect of sildenafil (1-40 mg kg(-1)) was investigated on clonic seizures induced by intravenous administration of GABA antagonists pentylenetetrazole (PTZ) and bicuculine and on generalized tonic seizures induced by intraperitoneal administration of high dose PTZ in male Swiss mice. The interaction of sildenafil-induced effects with NO-cGMP pathway was examined using nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), NOS substrate L-arginine, NO donor, sodium nitroprusside (SNP) and guanylyl cyclase inhibitor methylene blue (MB). Sildenafil induced a dose-dependent proconvulsant effect in both models of clonic, but not generalized tonic type of seizures. Pretreatment with either MB or L-NAME inhibited the proconvulsant effect of sildenafil, indicating the mediation of this effect by NO-cGMP pathway. In addition, a subeffective dose of sildenafil induced an additive proconvulsant effect when combined with either L-arginine or SNP. Sildenafil induces a proconvulsant effect on clonic seizure threshold that interacts with both exogenously and endogenously released NO and may be linked to activation of NO-cGMP pathway.
 ...
PMID:The proconvulsant effect of sildenafil in mice: role of nitric oxide-cGMP pathway. 1647 13

The urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular (1)H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate-nitric oxide-cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.
 ...
PMID:Neurological implications of urea cycle disorders. 1803 89

Activity-dependent neuroprotective protein (ADNP) is widely distributed in the cytoplasm of neurons and astrocytes of the hippocampus. Kainic acid (KA)-induced seizures increases neuronal nitric oxide synthase (nNOS) in neurons and inducible NOS (iNOS) in glia cells which coincides with a reduction in ADNP in the hippocampus. Inhibitors of NOS or soluble guanylyl cyclase (sGC) activity reduce ADNP under basal conditions in the absence of seizures. Treating animals with these inhibitors prior to KA-induced seizure, in particular, L-NAME (N(G)-nitro-l-arginine methyl ester), advances the onset of the first seizure but reverses the loss of ADNP by 3 days after the first seizure. This suggests that the NO-cGMP pathway has a role in regulating ADNP under both basal physiological conditions and in the pathophysiological changes produced during epileptogenesis.
 ...
PMID:Regulation of activity-dependent neuroprotective protein (ADNP) by the NO-cGMP pathway in the hippocampus during kainic acid-induced seizure. 1837 35

The present study was performed to examine the involvement of nitric oxide (NO) signaling pathway in the anti-convulsant effect of adenosine against pentylenetetrazol seizure threshold in mice. Minimal dose of pentylenetetrazol (i.v., mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of convulsions was recorded as an index of seizure threshold. Adenosine (100 or 200 mg/kg i.p.) produced a significant increase in the seizure threshold for convulsions induced by pentylenetetrazol i.v. infusion. The anti-convulsant effect of adenosine (100 mg/kg i.p.) was prevented by either L-arginine (50 mg/kg i.p.) [substrate for nitric oxide synthase (NOS)] or sodium nitroprusside (3 mg/kg i.p.) [a NO donor]. On the other hand, N(G)-nitro-L-arginine methyl ester (L-NAME, 2.5 mg/kg i.p.) [a non-selective NOS inhibitor] or 7-nitroindazole (7-NI) (25 mg/kg i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] potentiated the anti-convulsant action of sub-effective dose of adenosine (50 mg/kg i.p.). Aminoguanidine (100 mg/kg i.p.) [a specific inducible NOS (iNOS) inhibitor] pre-treatment was not effective in inducing anti-convulsant effect with sub-effective dose of adenosine (50 mg/kg i.p.). Furthermore, the increase in seizure threshold elicited by adenosine (100 mg/kg i.p.) was also inhibited by concomitant administration with sildenafil (5 mg/kg i.p.) [phosphodiesterase 5 inhibitor]. In contrast, treatment of mice with methylene blue (1 mg/kg i.p.) [a direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] failed to induce anti-convulsant action with adenosine (50 mg/kg i.p.) against pentylenetetrazol i.v. infusion. The results demonstrated that the anti-convulsant action of adenosine in the pentylenetetrazol i.v. seizure threshold paradigm may possibly involve an interaction with the L-arginine-NO-cGMP pathway which may be secondary to the activation of adenosine receptors.
 ...
PMID:Nitric oxide signaling pathway in the anti-convulsant effect of adenosine against pentylenetetrazol-induced seizure threshold in mice. 1845 33

Nitric oxide (NO) modulates synaptic transmission, and its level is elevated during epileptic activity in animal models of epilepsy. However, the role of NO for development and maintenance of epileptic activity is controversial. We studied this aspect in rat organotypic hippocampal slice cultures and acute hippocampal-entorhinal cortex slices from wild-type and neuronal NO synthase (nNOS) knock-out mice combining electrophysiological and fluorescence imaging techniques. Slice cultures contained nNOS-positive neurons and an elaborated network of nNOS-positive fibers. Lowering of extracellular Mg(2+) concentration led to development of epileptiform activity and increased NO formation as revealed by NO-selective probes, 4-amino-5-methylamino-2',7'-difluorofluorescein and 1,2-diaminoanthraquinone sulfate. NO deprivation by NOS inhibitors and NO scavengers caused depression of both EPSCs and IPSCs and prevented initiation of seizure-like events (SLEs) in 75% of slice cultures and 100% of hippocampal-entorhinal cortex slices. This effect was independent of the guanylyl cyclase/cGMP pathway. Suppression of SLE initiation in acute slices from mice was achieved by both the broad-spectrum NOS inhibitor N-methyl-L-arginine acetate and the nNOS-selective inhibitor 7-nitroindazole, whereas inhibition of inducible NOS by aminoguanidine was ineffective, suggesting that nNOS activity was crucial for SLE initiation. Additional evidence was obtained from knock-out animals because SLEs developed in a significantly lower percentage of slices from nNOS(-/-) mice and showed different characteristics, such as prolongation of onset latency and higher variability of SLE intervals. We conclude that enhancement of synaptic transmission by NO under epileptic conditions represents a positive feedback mechanism for the initiation of seizure-like events.
 ...
PMID:Endogenous nitric oxide is a key promoting factor for initiation of seizure-like events in hippocampal and entorhinal cortex slices. 1957 Nov 47

In order to assess the role of nitric oxide/cyclicGMP signaling pathway in the anticonvulsant effect of benzodiazepines, we studied the potential interaction of a phosphodiesterase type 5 inhibitor, sildenafil with the effect of diazepam on a mouse model of clonic seizures induced by intravenous infusion of GABA antagonist, pentylenetetrazole (PTZ). Administration of sildenafil (10 mg/kg; per se effective on seizure threshold) could abolish the anticonvulsive effect of diazepam, and a subeffective dose (5 mg/kg), when added to NO precursor L-arginine (50 mg/kg) could cause the same effect. Conversely, subeffective doses of diazepam (0.02 mg/kg) and NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 5 mg/kg), administered together, reversed the proconvulsive effect of sildenafil. Our findings indicate that the enhancement of NO/cGMP signaling pathway by sildenafil attenuates the anticonvulsant effect of the benzodiazepine prototype, diazepam. This suggests that the effects of facilitating GABA(A)-mediated inhibition and modulating NO pathways are additive and there might be a role for NO pathway in benzodiazepine effect against PTZ-induced seizures in mice.
 ...
PMID:The interaction of sildenafil with the anticonvulsant effect of diazepam. 1959 87

It has been reported that N-methyl-D-aspartate receptor (NMDAR)-triggered neurotoxicity is related to excessive Ca(2+) loading and an increase in nitric oxide (NO) concentration. However, the molecular mechanisms that underlie these events are not completely understood. NMDARs and neuronal NO synthase each binds to the scaffolding protein postsynaptic density (PSD)-93 through its PDZ domains. In this study, we determined whether PSD-93 plays a critical role in NMDAR/Ca(2+)/NO-mediated neurotoxicity. We found that the targeted disruption of the PSD-93 gene attenuated the neurotoxicity triggered by NMDAR activation, but not by non-NMDAR activation, in cultured mouse cortical neurons. PSD-93 deficiency reduced the amount of NMDAR subunits NR2A and NR2B in synaptosomal fractions from the cortical neurons and significantly prevented NMDA-stimulated increases in cyclic guanosine 3',5'-monophosphate and Ca(2+) loading in the cortical neurons. These findings indicate that PSD-93 deficiency could block NMDAR-triggered neurotoxicity by disrupting the NMDAR-Ca(2+)-NO signaling pathway and reducing expression of synaptic NR2A and NR2B. Since NMDARs, Ca(2+), and NO play a critical role during the development of brain trauma, seizures, and ischemia, the present work suggests that PSD-93 might contribute to molecular mechanisms of neuronal damage in these brain disorders.
 ...
PMID:Postsynaptic density-93 deficiency protects cultured cortical neurons from N-methyl-D-aspartate receptor-triggered neurotoxicity. 2009 70

Lithium is still the mainstay in the treatment of affective disorders as a mood stabilizer. Lithium also shows some anticonvulsant properties. While the underlying mechanisms of action of lithium are not yet exactly understood, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of lithium is mediated via NO-cGMP pathway. Injection of a single effective dose of lithium chloride (25 mg/kg) intraperitoneally (i.p.) increased significantly the seizure threshold (P<0.01). The anticonvulsant properties of the effective dose of lithium were prevented by pre-treatment with the per se non-effective doses of L-ARG [the substrate for nitric oxide synthase; NOS] (30 and 50 mg/kg) or sildenafil [a phosphodiesterase 5 inhibitor] (10 and 20 mg/kg). L-NAME [a non-specific NOS inhibitor] (5, 15 and 30 mg/kg), 7-NI [a specific neural NOS inhibitor] (30 and 60 mg/kg) or MB [a guanylyl cyclase inhibitor] (0.5 and 1 mg/kg) augmented the anticonvulsant effect of a sub-effective dose of lithium (10 mg/kg, i.p.). Whereas several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of lithium. Our findings demonstrated that nitric oxide-cyclic GMP pathway could be involved in the anticonvulsant properties of the lithium chloride. In addition, the role of constitutive NOS versus inducible NOS is prominent in this phenomenon.
 ...
PMID:Involvement of nitric oxide-cGMP pathway in the anticonvulsant effects of lithium chloride on PTZ-induced seizure in mice. 2030 10

The effects of pretreatment of mice with some drugs which modify GABAergic neurotransmission on the convulsions and cerebellar cyclic nucelotide level changes induced by the subsequent intracerebroventricular administration of 4-isopropyl-2,6,7-trioxa-1-phosphabicyclo(2,2,2)octane-1-oxide (IPTBO) have been studied. Muscimol, pentobarbitone and diazepam reduced the number of animals convulsing and prolonged the time to onset of convulsions in those animals which did, whereas baclofen and ?-acetylenic GABA had no effect on the number of animals convulsing but did prolong seizure latency. All the drugs except baclofen prevented the increase in cyclic GMP concentrations following IPTBO treatment. Pentobarbitone, baclofen and ?-acetylenic GABA caused significant increases in the concentrations of cyclic AMP, whereas there was no marked effect of treatment with IPTBO alone on the levels of this nucleotide: however, IPTBO reduced the extent of the increases produced by the drugs. The results are discussed in the context of the mechanism of action of IPTBO and the involvement of GABAergic neurotransmission in convulsant and anticonvulsant activities.
 ...
PMID:The effect of various drug pretreatments on the convulsions and cerebellar cyclic nucleotide changes induced by the convulsant 4-isopropyl-2,6,7-trioxa-1-phosphatbicyclo(2,2,2)octane-1-oxide(IPTBO). 2048 40


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