UMLS:C0038220 - FACTA Search

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Query: UMLS:C0038220 (status epilepticus)
7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABA, the main inhibitory neurotransmitter in the adult brain, exerts its effects through multiple GABA(A) receptor subtypes with different pharmacological profiles, the alpha subunit variant mainly determining the binding properties of benzodiazepine site on the receptor protein. In adult experimental epileptic animals and in humans with epilepsy, increased excitation, i.e. seizures, alters GABA(A) receptor subunit expression leading to changes in the receptor structure, function, and pharmacology. Whether this also occurs in the developing brain, in which GABA has a trophic, excitatory effect, is not known. We have now applied autoradiography to study properties of GABA(A)/benzodiazepine receptors in 9-day-old rats acutely (6 h) and sub-acutely (7 days) after kainic acid-induced status epilepticus by analyzing displacement of [(3)H]flunitrazepam binding by zolpidem, a ligand selective for the alpha1beta2gamma2 receptor subtype. Regional changes in the binding properties were further corroborated at the cellular level by immunocytochemistry. The results revealed that status epilepticus significantly decreased displacement of [(3)H]flunitrazepam binding by zolpidem 6 h after the kainic acid-treatment in the dentate gyrus of the hippocampus, parietal cortex, and thalamus, and in the hippocampal CA3 and CA1 cell layers 1 week after the treatment. Our results suggest that status epilepticus modifies region-specifically the pharmacological properties of GABA(A) receptors, and may thus disturb the normal, strictly developmentally-regulated maturation of zolpidem-sensitive GABA(A) receptors in the immature rat brain. A part of these changes could be due to alterations in the cell surface expression of receptor subtypes.
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PMID:Status epilepticus alters zolpidem sensitivity of [3H]flunitrazepam binding in the developing rat brain. 1736 Jan 22

GABA(A) receptors have dual functions during development. They depolarize immature neurons but hyperpolarize more mature neurons. This functional switch has been attributed to age-related differences in the relative abundance of cation chloride cotransporters, such as KCC2 and NKCC1, which regulate chloride homeostasis. Certain insults, such as trauma, ischemia, and seizures, if they occur when GABA(A)ergic signaling is hyperpolarizing, such as in the adult brain, can lead to reappearance of the immature, depolarizing synaptic responses to GABA(A) receptor activation. In certain cases, this has been associated with either reduced expression of KCC2 or increase in NKCC1. In epilepsy, the depolarizing effects of GABA(A) receptors have been proposed to be important for the acquisition and/or maintenance of the epileptic state. Using the kainic acid model of status epilepticus, we have studied the effects of repetitive neonatal episodes of status epilepticus on the expression of cation chloride cotransporter KCC2 in the neonatal hippocampus. In contrast to adults, seizures increased KCC2 mRNA expression in the CA3 region of the neonatal hippocampus. The contrasting patterns of regulation of KCC2 by seizures in mature and immature neurons may be one of the age-related factors that protect the neonatal brain against the development of epilepsy.
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PMID:Developmental patterns in the regulation of chloride homeostasis and GABA(A) receptor signaling by seizures. 1791 May 76

A rapid modification in the postsynaptic gamma-aminobutyric acid (GABA(A)) receptor population occurs during the prolonged seizures of status epilepticus (SE). This rapid modification contributes to a reduction in GABA-mediated inhibition and the development of benzodiazepine pharmacoresistance. Previous hypotheses to explain the modification have included an alteration in the structural composition or posttranslational modification of the receptors. In a cultured hippocampal neuron model, we found that there was differential subcellular distribution of GABA(A) receptor subunits and that the constitutive internalization of GABA(A) receptors containing a beta2/3 subunit was rapid and activity-dependent. Based on this finding, we posit that an activity-dependent increase in the rate of internalization of synaptic GABA(A) receptors during SE contributes to the reduction in inhibitory transmission and the development of benzodiazepine pharmacoresistance.
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PMID:GABA(A) receptor internalization during seizures. 1791 May 89

A study was made of the "rundown" of GABA(A) receptors, microtransplanted to Xenopus oocytes from surgically resected brain tissues of patients afflicted with drug-resistant human mesial temporal lobe epilepsy (mTLE). Cell membranes, isolated from mTLE neocortex specimens, were injected into frog oocytes that rapidly incorporated functional GABA(A) receptors. Upon repetitive activation with GABA (1 mM), "epileptic" GABA(A) receptors exhibited a GABA(A)-current (I(GABA)) rundown that was significantly enhanced by Zn(2+) (</=250 microM), and practically abolished by the high-affinity GABA(A) receptor inverse agonist SR95531 (gabazine; 2.5-25 microM). Conversely, I(GABA) generated by "control" GABA(A) receptors microtransplanted from nonepileptic temporal lobe, lesional TLE, or authoptic disease-free tissues remained stable during repetitive stimulation, even in oocytes treated with Zn(2+). We conclude that rundown of mTLE epileptic receptors depends on the presence of "phasic GABA(A) receptors" that have low sensitivity to antagonism by Zn(2+). Additionally, we found that GABA(A) receptors, microtransplanted from the cerebral cortex of adult rats exhibiting recurrent seizures, caused by pilocarpine-induced status epilepticus, showed greater rundown than control tissue, an event also occurring in patch-clamped rat pyramidal neurons. Rundown of epileptic rat receptors resembled that of human mTLE receptors, being enhanced by Zn(2+) (40 microM) and sensitive to the antiepileptic agent levetiracetam, the neurotrophin brain-derived neurotrophic factor, and the phosphatase blocker okadaic acid. Our findings point to the rundown of GABA(A) receptors as a hallmark of TLE and suggest that modulating tonic and phasic mTLE GABA(A) receptor activity may represent a useful therapeutic approach to the disease.
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PMID:GABA(A)-current rundown of temporal lobe epilepsy is associated with repetitive activation of GABA(A) "phasic" receptors. 1808 39

GABA(A) receptor-mediated inhibition depends on the maintenance of intracellular Cl- concentration ([Cl-]in) at low levels. In neurons in the developing CNS, [Cl-]in is elevated, E(GABA) is depolarizing, and GABA consequently is excitatory. Depolarizing GABAergic synaptic responses may be recapitulated in various neuropathological conditions, including epilepsy. In the present study, rat hippocampal dentate granule cells were recorded using gramicidin perforated patch techniques at varying times (1-60 d) after an epileptogenic injury, pilocarpine-induced status epilepticus (STEP). In normal, non-epileptic animals, these strongly inhibited dentate granule cells act as a gate, regulating hippocampal excitation, controlling seizure initiation and/or propagation. For 2 weeks after STEP, we found that E(GABA) was positively shifted in granule cells. This shift in E(GABA) altered synaptic integration, increased granule cell excitability, and resulted in compromised "gate" function of the dentate gyrus. E(GABA) recovered to control values at longer latencies post-STEP (2-8 weeks), when animals had developed epilepsy. During this period of shifted E(GABA), expression of the Cl- extruding K+/Cl- cotransporter, KCC2 was decreased. Application of the KCC2 blocker, furosemide, to control neurons mimicked E(GABA) shifts evident in granule cells post-STEP. Furthermore, post-STEP and furosemide effects interacted occlusively, both on E(GABA) in granule cells, and on gatekeeper function of the dentate gyrus. This suggests a shared mechanism, reduced KCC2 function. These findings demonstrate that decreased expression of KCC2 persists for weeks after an epileptogenic injury, reducing inhibitory efficacy and enhancing dentate granule cell excitability. This pathophysiological process may constitute a significant mechanism linking injury to the subsequent development of epilepsy.
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PMID:Disrupted dentate granule cell chloride regulation enhances synaptic excitability during development of temporal lobe epilepsy. 1809 40

Early in development, the depolarizing GABA(A)ergic signaling is needed for normal neuronal differentiation. It is shown here that hyperpolarizing reversal potentials of GABA(A)ergic postsynaptic currents (E(GABA)) appear earlier in female than in male rat CA1 pyramidal neurons because of increased potassium chloride cotransporter 2 (KCC2) expression and decreased bumetanide-sensitive chloride transport in females. Three episodes of neonatal kainic acid-induced status epilepticus (3KA-SE), each elicited at postnatal days 4 (P4)-P6, reverse the direction of GABA(A)ergic responses in both sexes. In males, 3KA-SE trigger a premature appearance of hyperpolarizing GABA(A)ergic signaling at P9, instead of P14. This is driven by an increase in KCC2 expression and decrease in bumetanide-sensitive chloride cotransport. In 3KA-SE females, E(GABA) transiently becomes depolarizing at P8-P13 because of increase in the activity of a bumetanide-sensitive NKCC1 (sodium potassium chloride cotransporter 1)-like chloride cotransporter. However, females regain their hyperpolarizing GABA(A)ergic signaling at P14 and do not manifest spontaneous seizures in adulthood. In maternally separated stressed controls, a hyperpolarizing shift in E(GABA) was observed in both sexes, associated with decreased bumetanide-sensitive chloride cotransport, whereas KCC2 immunoreactivity was increased in males only. GABA(A) receptor blockade at the time of 3KA-SE or maternal separation reversed their effects on E(GABA). These data suggest that the direction of GABA(A)-receptor signaling may be a determining factor for the age and sex-specific effects of prolonged seizures in the hippocampus, because they relate to normal brain development and possibly epileptogenesis. These effects differ from the consequences of severe stress.
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PMID:Dissociated gender-specific effects of recurrent seizures on GABA signaling in CA1 pyramidal neurons: role of GABA(A) receptors. 1912 13

The epileptic brain is characterized by increased susceptibility to neuronal hyperexcitability. The rat lithium-pilocarpine model, which mimics many features of temporal lobe epilepsy, has been used to study processes leading to the development of recurrent seizures. After a prolonged seizure episode, termed status epilepticus (SE), neural changes occur during a period known as epileptogenesis and include neuronal cell death, reactive gliosis, axonal sprouting, and synaptogenesis. Extracellular matrix adhesion molecules are important regulators of synaptogenesis and axonal sprouting resulting from SE. SC1, also known as hevin, is an antiadhesive extracellular matrix molecule that localizes to synapses in the mammalian brain. In this study, the distribution of SC1 protein in neurons following SE was examined using the lithium-pilocarpine model. SC1 protein levels in neuronal cell bodies showed a transient decrease at 1 day post-SE, which coincided with an increase of SC1 in the synapse-rich neuropil that was identified with the synaptic marker synaptophysin. Immunoelectron microscopy confirmed the decrease of SC1 signal in neurons at 1 day post-SE and showed that SC1 remained localized to postsynaptic elements throughout the seizure time course. Increased colocalization of SC1 was detected with the excitatory synaptic markers vesicular glutamate transporter 1 (VGLUT1), AMPA receptor subunit GluR1, and N-methyl-D-aspartate receptor subunit NR1, but not with the inhibitory synaptic markers vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) and GABA(A) receptor subunit beta2 (GABA(A) beta2), which could reflect enhanced association of SC1 with excitatory synapses. These findings suggest that SC1 may be involved in synaptic modifications underlying epileptogenesis.
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PMID:The extracellular matrix protein SC1/hevin localizes to excitatory synapses following status epilepticus in the rat lithium-pilocarpine seizure model. 1848 94

Epidemiological data indicate that 20-40% of the patients with epilepsy are refractory to treatment with antiepileptic drugs (AEDs). The mechanisms underlying pharmacoresistance in epilepsy are unclear, but several plausible hypotheses have emerged, including loss of AED target sensitivity in the epileptic brain, decreased AED concentrations at brain targets because of localized overexpression of drug efflux transporters in epileptogenic brain tissue, and network alterations in response to brain damage associated with epilepsy. Rat models of epilepsy in which part of the animals are resistant to treatment with AEDs offer a means to investigate the mechanisms underlying AED resistance. In the present study, AED-responsive and AED-resistant rats were selected from a model in which spontaneous recurrent seizures develop after a status epilepticus induced by electrical stimulation of the basolateral amygdala. For selection into responders and nonresponders, epileptic rats were treated over two weeks by phenobarbital. Subsequent histological examination showed neurodegeneration of the CA1, CA3 and dentate hilus in only one of eight responders but five of six nonresponders (P=0.0256). Based on previous studies in AED-resistant rats of this model, we hypothesized that changes in the structure and function of inhibitory GABA(A) receptors may contribute to drug resistance. We therefore analyzed the distribution and expression of several GABA(A) receptor subunits (alpha1, alpha2, alpha 3, alpha 4, alpha 5, beta2/3, and gamma 2) immunohistochemically with specific antibodies in the hippocampal formation of responders, nonresponders and nonepileptic controls. In nonresponders, decreased subunit staining was observed in CA1, CA2, CA3, and dentate gyrus, whereas much less widespread alterations were determined in responders. Furthermore, upregulation of the alpha 4-subunit was observed in the CA1 of nonresponders. Our data suggest that alterations in GABA(A) receptor subtypes may be involved in resistance to AEDs.
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PMID:Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy. 1856 4

GABA(A) receptors have an age-adapted function in the brain. During early development, they mediate excitatory effects resulting in activation of calcium sensitive signaling processes that are important for the differentiation of the brain. In more mature stages of development and in adults, GABA(A) receptors transmit inhibitory signals. The maturation of GABA(A) signaling follows sex-specific patterns, which appear to also be important for the sexual differentiation of the brain. The inhibitory effects of GABA(A) receptor activation have been widely exploited in the treatment of conditions where neuronal silencing is necessary. For instance, drugs that target GABA(A) receptors are the mainstay of treatment of seizures. Recent evidence suggests however that the physiology and function of GABA(A) receptors changes in the brain of a subject that has epilepsy or status epilepticus.This review will summarize the physiology of and the developmental factors regulating the signaling and function of GABA(A) receptors; how these may change in the brain that has experienced prior seizures; what are the implications for the age and sex specific treatment of seizures and status epilepticus. Finally, the implications of these changes for the treatment of certain forms of medically refractory epilepsies and status epilepticus will be discussed.
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PMID:GABA(A) receptors in normal development and seizures: friends or foes? 1930 85

Retrospective studies suggest that precipitating events such as prolonged seizures, stroke, or head trauma increase the risk of developing epilepsy later in life. The process of epilepsy development, known as epileptogenesis, is associated with changes in the expression of a myriad of genes. One of the major challenges for the epilepsy research community has been to determine which of these changes contributes to epileptogenesis, which may be compensatory, and which may be noncontributory. Establishing this for any given gene is essential if it is to be considered a therapeutic target for the prevention or treatment of epilepsy. Our laboratories have examined alterations in gene expression related to inhibitory neurotransmission that have been proposed as contributing factors in epileptogenesis. The GABA(A) receptor mediates most fast synaptic inhibition, and changes in GABA(A) receptor subunit expression and function have been reported in adult animals beginning immediately after prolonged seizures (status epilepticus [SE]) and continue as animals become chronically epileptic. Prevention of GABA(A) receptor subunit changes after SE using viral gene transfer inhibits development of epilepsy in an animal model, suggesting that these changes directly contribute to epileptogenesis. The mechanisms that regulate differential expression of GABA(A) receptor subunits in hippocampus after SE have recently been identified, and include the CREB-ICER, JAK-STAT, BDNF, and Egr3 signaling pathways. Targeting signaling pathways that alter the expression of genes involved in epileptogenesis may provide novel therapeutic approaches for preventing or inhibiting the development of epilepsy after a precipitating insult.
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PMID:Alteration of epileptogenesis genes. 1933 25

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