Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liposomes (LIPO), which are concentric lipid layers alternating with aqueous compartments, have been suggested as a potential carrier for various drugs. In the previous studies, we have demonstrated that anticonvulsant drugs such as valproic acid, phenytoin, and DN-1417 (an analog of thyrotropin-releasing hormone) entrapped into LIPO exert more prominent therapeutic efficacy than parent drugs. In the present study, we examined the comparative effects of Lidocaine (LDCA) which acts as a proconvulsant as well as an anticonvulsant, and LIPO-entrapped LDCA (LDCA-L) on limbic status epilepticus originating in the amygdala (AM) of rats. LDCA (LDCA hydrochloride) was dissolved in distilled water as a vehicle at a concentration of 2.5 mg/ml or 10 mg/ml. LIPO and LDCA-L were prepared from L-alpha-phosphatidylcholine, cholesterol, and stearylamine. Status epilepticus was induced by intra-AM injection of combined dibutyryl (db)-cAMP-200 micrograms/ethylene diaminetetraacetic acid (EDTA)-67.2 micrograms through the implanted cannula. The animals were divided into 4 groups which received vehicle (n = 6), LIPO (n = 5), LDCA (n = 9), and LDCA-L (n = 10). LDCA group was subdivided into 5 mg/kg (n = 4) and 20 mg/kg (n = 5) groups. LDCA-L group was treated with 5mg/kg (n = 4) or 20mg/kg (n = 6). All drugs were intravenously given at a volume of 2ml/kg via teflon tube previously inserted into cervical vein 30 min after db-cAMP/EDTA injection. Vehicle or LIPO alone did not alter the pattern of electroclinical ictal responses produced by intra-AM injection of db-cAMP/EDTA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effect of liposome-entrapped lidocaine on limbic status epilepticus in rats]. 165 83

Recent studies have demonstrated that intramuscular administration of thyrotropin-releasing hormone (TRH) or its analogue improves various clinical aspects of intractable epilepsy such as Lennox-Gastaut syndrome, West syndrome, and myoclonus epilepsy. Other clinical studies reported efficient property of intravenous TRH against status epilepticus. However, it is also true that intravenous TRH produces epileptic seizures in patients with epilepsy or organic brain damage. Thus, the utility of intravenous TRH for the treatment of status epilepticus seems to be equivocal. To further explore the problem in this regard, we examined the effect of TRH on limbic status epilepticus in rats. Thirty-eight male Wistar rats weighing 180-220g were used. Status epilepticus was induced by intracerebral injection of a combination of 200 micrograms of dibutyryl-cAMP (db-cAMP) and 67.2ng of ethylenediaminetetraacetic acid (EDTA) into the amygdala (AM) through an implanted cannula. 30 min later, TRH or vehicle (distilled water) was administered intravenously (i.v.) or intracerebroventricularly (i.c.v.). Although 3 mg/kg of TRH (n = 9), when injected i.v., did not alter the pattern of electroclinical ictal responses induced by db-cAMP/EDTA, 25 mg/kg (n = 5) and 50 mg/kg (n = 5) of TRH significantly exaggerated EEG and/or behavioral ictal seizures, beginning immediately after the injection and lasting for more than 30 min. With 50 mg/kg of TRH, the exaggerated seizure patterns were followed by marked suppression of electroclinical seizures. 50 micrograms of i.c.v. TRH (n = 5), like higher doses of i.v. TRH, caused a slight, but not a significant, build up of electroclinical ictal seizures, beginning immediately after the injection and lasting for about 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of thyrotropin-releasing hormone (TRH) on status epilepticus in rats]. 190 68

The behavioral and electrographic effects of acoustic stimulation (100 dB) and injection of dibutyryl cyclic AMP (cAMP, 10 nmol) into the inferior colliculus were studied in normal and genetically epilepsy-prone (GEPR-9) rats. Acoustic stimulations induced behavioral seizures only in GEPR-9 rats; the seizures were associated with electrographic epileptiform discharges recorded from the inferior colliculus. Injections of dibutyryl cAMP into the inferior colliculus caused wild running episodes resembling the initial phase of audiogenic seizures in both groups. However, in GEPR-9 rats these episodes progressed to significantly more severe seizures than in normal rats and the convulsions culminated into status epilepticus. During drug-induced seizures, epileptiform activity was present in the inferior colliculus in both groups. The seizure generalization latency was markedly shorter in GEPR-9 rats than in normals. Furthermore, in GEPR-9 rats, the seizure generalization latency was in the same range with either acoustic stimulation-induced or dibutyryl cAMP-induced seizures. The data suggest that the increased susceptibility of genetically epilepsy-prone rats to acoustic stimuli may be related to a malfunction of the cyclic AMP system within the inferior colliculus.
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PMID:Different behavioral and electrographic effects of acoustic stimulation and dibutyryl cyclic AMP injection into the inferior colliculus in normal and in genetically epilepsy-prone rats. 254 56

The objective of the present experiments was to study metabolic correlates to the localization of neuronal lesions during sustained seizures. To that end, status epilepticus was induced by i.v. administration of bicuculline in immobilized and artificially ventilated rats, since this model is known to cause neuronal cell damage in cerebral cortex and hippocampus but not in the cerebellum. After 20 or 120 min of continuous seizure activity, brain tissue was frozen in situ through the skull bone, and samples of cerebral cortex, hippocampus, and cerebellum were collected for analysis of glycolytic metabolites, phosphocreatine (PCr), ATP, ADP, AMP, and cyclic nucleotides. After 20 min of seizure activity, the two "vulnerable" structures (cerebral cortex and hippocampus) and the "resistant" one (cerebellum) showed similar changes in cerebral metabolic state, characterized by decreased tissue concentrations of PCr, ATP, and glycogen, and increased lactate concentrations and lactate/pyruvate ratios. In all structures, though, the adenylate energy charge remained close to control. At the end of a 2-h period of status epilepticus, a clear deterioration of the energy state was observed in the cerebral cortex and the hippocampus, but not in the cerebellum. The reduction in adenylate energy charge in the cortex and hippocampus was associated with a seemingly paradoxical decrease in tissue lactate levels and with failure of glycogen resynthesis (cerebral cortex). Experiments with infusion of glucose during the second hour of a 2-h period of status epilepticus verified that the deterioration of tissue energy state was partly due to reduced substrate supply; however, even in animals with adequate tissue glucose concentrations, the energy charge of the two structures was significantly lowered. The cyclic nucleotides (cAMP and cGMP) behaved differently. Thus, whereas cAMP concentrations were either close to control (hippocampus and cerebellum) or moderately increased (cerebral cortex), the cGMP concentrations remained markedly elevated throughout the seizure period, the largest change being observed in the cerebellum. It is concluded that although the localization of neuronal damage and perturbation of cerebral energy state seem to correlate, the results cannot be taken as evidence that cellular energy failure is the cause of the damage. Thus, it appears equally probable that the pathologically enhanced neuronal activity (and metabolic rate) underlies both the cell damage and the perturbed metabolic state. The observed changes in cyclic nucleotides do not appear to bear a causal relationship to the mechanisms of damage.
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PMID:Metabolic changes in cerebral cortex, hippocampus, and cerebellum during sustained bicuculline-induced seizures. 729 97

We produced limbic status epilepticus in rats by injecting a combination of dibutyryl-cAMP (db-cAMP) and ethylenediaminetetraacetic acid (EDTA) into the amygdala (AM). Thirty minutes after intra-AM db-cAMP/EDTA injection, thyrotropin-releasing hormone (TRH) was administered intravenously or intracerebroventricularly. Intravenous TRH (3, 25, 50 mg/kg) produced immediate activation of electroclinical seizures, lasting for 25-45 min. In some animals which showed this seizure activation, complete seizure suppression occurred 55-70 min after the TRH treatment. Similar activation of ictal seizures with delayed seizure suppression was obtained after intracerebroventricular TRH (25, 50 micrograms). The findings suggest that the effects of intravenous TRH are due to its central action and that the use of intravenous TRH is not a promising approach for the treatment of status epilepticus.
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PMID:The effect of thyrotropin-releasing hormone (TRH) on limbic status epilepticus in rats. 780 43

Status epilepticus was induced in rats by injecting a combination of dibutyryl-cAMP (db-cAMP) and ethylenediaminetetraacetic acid (EDTA) into the amygdala (AM), and the effect of phenytoin (PHT), entrapped in liposomes (PHT-L) and given intravenously at 40 mg/kg, on the spiking activity of the AM epileptogenic focus was examined. Electroencephalograms were recorded from the db-cAMP/EDTA-injected AM and the bilateral sensorimotor cortices. One dose of PHT-L, given 30 min after intra-AM db-cAMP, produced immediate and transient seizure suppression, but did not suppress the sequential spiking activity, which lasted for more than 5 h. In contrast, two doses of PHT-L, given 30 and 60 min after intra-AM db-cAMP/EDTA, produced delayed and local suppression of AM discharges, and immediate and transient seizure suppression was also observed. The AM discharges began to be suppressed about 100 min after the second injection of PHT-L injection, with no overt change occurring in cortical spiking activity. This was followed by total seizure suppression about 170 min after the second PHT-L injection. This effect was not observed after one or two injections of PHT alone. When horseradish peroxidase (HRP), to which the blood-brain barrier is impermeable, was entrapped in liposomes (HRP-L) and given intravenously 30 min after intra-AM db-cAMP/EDTA, an accumulation of HRP was found in the db-cAMP/EDTA-injected AM in 2 of the 5 animals tested. With 2 doses of HRP-L given 30 and 60 min after intra-AM db-cAMP/EDTA, the local augmentation of HRP in the AM was found in all 5 of the 5 animals tested. Our findings suggest that: (1) the AM epileptogenic focus created by db-cAMP/EDTA has a high affinity for liposomes, and this factor participates in the local suppression of AM discharges by PHT-L, and (2) two injections of PHT-L are required for the AM to gather an effective amount of PHT-L.
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PMID:Liposome-entrapped phenytoin locally suppresses amygdaloid epileptogenic focus created by db-cAMP/EDTA in rats. 871 31

Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters. There are three families of ionotropic receptors with intrinsic cation permeable channels [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate]. There are three groups of metabotropic, G protein-coupled glutamate receptors (mGluR) that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Glutamate is the most abundant amino acid in the diet. There is no evidence for brain damage in humans resulting from dietary glutamate. A kainate analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate, by activating NMDA, AMPA or mGluR1 receptors, may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury. It may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's chorea. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Such compounds are undergoing testing in humans, but therapeutic efficacy has yet to be established. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis.
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PMID:Glutamate as a neurotransmitter in the brain: review of physiology and pathology. 1073 72

Malnutrition and/or seizure in the developing brain cause hippocampal damages. However, underlying mechanisms remain unclear. The malnutrition group (MN) subjected with malnutrition alone was culled to 20-22 rats per dam on postnatal day 1 (P1). The rats subjected to lithium-pilocarpine (Li/PC)-induced status epilepticus at P21 were grouped as the SE group. The rats subjected to malnutrition and subsequent status epilepticus were grouped as the MS group. Visual-spatial memory test using the Morris water maze task was performed at P80. Following behavioral tests, the hippocampus was evaluated for histological lesions and phosphorylated cAMP-responsive, element-binding protein at serine-133 (pCREB(Ser-133)), an important transcription factor underlying learning and memory in the mammalian brain. Here, the MN group exhibited decreased body weight at P21. There was no significant difference in the seizure duration and mortality between the SE and MS groups. In adulthood (P80), both the SE and MS groups showed the spatial learning deficit, hippocampal cell loss and decreased pCREB(Ser133) level within hippocampal CA1 region. Although the MN group demonstrated a decreased level of pCREB(Ser133), no distinguishable changes in the cognitive deficit and hippocampal neuronal loss were detected. Collectively, the present results suggest that early-life malnutrition led to a reduced phosphorylation of CREB(Ser133) in hippocampal CA1 in the absence of the long-term spatial learning deficit. This decreased phosphorylation of CREB(Ser133) could suggest that cascades of signal transduction responsible for the phosphorylation of CREB(Ser133) might be disturbed by early-life malnutrition. In addition, malnutrition caused no discernible synergistic effects on Li/PC-induced status epilepticus.
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PMID:Long-term effects of early-life malnutrition and status epilepticus: assessment by spatial navigation and CREB(Serine-133) phosphorylation. 1460 61

Effects of cAMP-activated protein kinases (PKA) on epileptic activity are at present studied in a model nervous system. Identified neurons in the buccal ganglia of the snail Helix pomatia were recorded with intracellular microelectrodes in a continuously perfused experimental chamber. Epileptiform activity appeared regularly in neuron B3 when the saline contained pentylenetetrazol (20-40 mM). Epileptiform activity consisted of a series of paroxysmal depolarization shifts (PDS). Epileptiform activity was quantified by calculating the percentage of PDS-duration of PDS-periods. High percentage of PDS-duration was regularly found 15-30 min after the start of treatment with pentylenetetrazol. Subsequently, percentage of PDS decreased spontaneously. Adding forskolin (50 microM) to the pentylenetetrazol-containing solution increased percentage of PDS-duration. The increase during forskolin corresponded to the amount of decrease which had taken place spontaneously before. During application of forskolin for up to 4 h, spontaneous PDS decrease was absent, i.e., epileptiform activity corresponded to status epilepticus. Forskolin was not able to induce epileptiform activity when applied without pentylenetetrazol. 1,6-Dideoxy-forskolin (50 microM) did not accelerate epileptiform activity. When pentylenetetrazol was applied twice (1 h each) separated by 2.5 h of control conditions, PDS decrease obtained during the first application was found to be largely preserved during control conditions. When forskolin was applied for 30 min in between both applications of pentylenetetrazol, the second response to pentylenetetrazol did not show a preserved PDS decrease. Results suggest that forskolin blocks an endogenous antiepileptic process and that activation of PKA can maintain epileptic activity and induce status epilepticus.
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PMID:Block of spontaneous termination of paroxysmal depolarizations by forskolin (buccal ganglia, Helix pomatia). 1617 48

Status epilepticus (SE) triggers neuronal death, reactive gliosis and remodeling of synaptic circuitry, thus leading to profound pathological alterations in CNS physiology. These processes are, in part, regulated by the rapid upregulation of both cytotoxic and cytoprotective genes. One pathway that may couple SE to transcriptionally dependent alterations in CNS physiology is the CREB (cAMP response element-binding protein)/CRE (cAMP response element) cascade. Here, we utilized the pilocarpine model of SE on a mouse strain transgenic for a CRE-reporter construct (beta-galactosidase) to begin to characterize how seizure activity regulates the activation state of the CREB/CRE pathway in both glia and neurons of the hippocampus. SE triggered a rapid (4-8 h post-SE) but transient increase in CRE-mediated gene expression in the neuronal sublayers. In contrast to neurons, SE induced a lasting increase (up to 20 days) in CRE-mediated transcription in both reactive astrocytes and microglia. CRE-mediated gene expression correlated with expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2). To examine the role of CREB in SE-induced COX-2 expression, we generated a transgenic mouse strain that expresses A-CREB, a potent repressor of CREB-dependent transcription. In these animals, the capacity of SE to stimulate COX-2 expression was markedly attenuated, indicating that CREB is a key intermediate in SE-induced COX-2 expression. Collectively these data show that SE triggers two waves of CREB-mediated gene expression, a transient wave in neurons and a long-lasting wave in reactive glial cells, and that CREB couples SE to COX-2 expression.
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PMID:CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticus. 1702 65


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