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)

NKCC1 and KCC2 are encoded by slc12 gene family and involved in the maintenance of intracellular chloride concentration which may be associated with epileptogenesis. In this study, we aimed to investigate the long-term expression profiles of NKCC1 and KCC2 in CA1 region in the mice model of lithium-pilocarpine induced status epilepticus (PISE) and their relationship with epileptogenesis. We found NKCC1 mRNA and proteins were up-regulated at 1 d, 14 d and 45 d after pilocarpine injection, while KCC2 was down-regulated. According to obtained results, there were some expressional changes of NKCC1 and KCC2. Deregulation of their expression may break the balance of intracellular and extracellular chloride concentration which contributes to the mechanism of hyperexcitability leading to seizures. Also it may provide new drug targets for development of new antiepileptic medicine.
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PMID:Long-term expressional changes of Na+ -K+ -Cl- co-transporter 1 (NKCC1) and K+ -Cl- co-transporter 2 (KCC2) in CA1 region of hippocampus following lithium-pilocarpine induced status epilepticus (PISE). 1855 34

Seizures that occur during the neonatal period do so with a greater frequency than at any other age, have profound consequences for cognitive and motor development, and are difficult to treat with the existing series of antiepileptic drugs. During development, gamma-aminobutyric acid (GABA)ergic neurotransmission undergoes a switch from excitatory to inhibitory due to a reversal of neuronal chloride (Cl()) gradients. The intracellular level of chloride ([Cl()](i)) in immature neonatal neurons, compared with mature adult neurons, is about 20-40 mM higher due to robust activity of the chloride-importing Na-K-2Cl cotransporter NKCC1, such that the binding of GABA to ligand-gated GABA(A) receptor-associated Cl() channels triggers Cl() efflux and depolarizing excitation. In adults, NKCC1 expression decreases and the expression of the genetically related chloride-extruding K-Cl cotransporter KCC2 increases, lowering [Cl()](i) to a level such that activation of GABA(A) receptors triggers Cl() influx and inhibitory hyperpolarization. The excitatory action of GABA in neonates, while playing an important role in neuronal development and synaptogenesis, accounts for the decreased seizure threshold, increased seizure propensity, and poor efficacy of GABAergic anticonvulsants in this age group. Bumetanide, a furosemide-related diuretic already used to treat volume overload in neonates, is a specific inhibitor of NKCC1 at low doses, can switch the GABA equilibrium potential of immature neurons from depolarizing to hyperpolarizing, and has recently been shown to inhibit epileptic activity in vitro and in vivo in animal models of neonatal seizures. The fundamental role of NKCC1 in establishing excitatory GABAergic neurotransmission in the neonate makes it a tempting target of a novel mechanism-based anticonvulsant strategy that could utilize the well-known pharmacology of bumetanide to help treat neonatal seizures.
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PMID:The bumetanide-sensitive Na-K-2Cl cotransporter NKCC1 as a potential target of a novel mechanism-based treatment strategy for neonatal seizures. 1875 24

In the nervous system, the intracellular chloride concentration ([Cl(-)](i)) determines the strength and polarity of gamma-aminobutyric acid (GABA)-mediated neurotransmission. [Cl(-)](i) is determined, in part, by the activities of the SLC12 cation-chloride cotransporters (CCCs). These transporters include the Na-K-2Cl cotransporter NKCC1, which mediates chloride influx, and various K-Cl cotransporters--such as KCC2 and KCC3-that extrude chloride. A precise balance between NKCC1 and KCC2 activity is necessary for inhibitory GABAergic signaling in the adult CNS, and for excitatory GABAergic signaling in the developing CNS and the adult PNS. Altered chloride homeostasis, resulting from mutation or dysfunction of NKCC1 and/or KCC2, causes neuronal hypoexcitability or hyperexcitability; such derangements have been implicated in the pathogenesis of seizures and neuropathic pain. [Cl(-)](i) is also regulated to maintain normal cell volume. Dysfunction of NKCC1 or of swelling-activated K-Cl cotransporters has been implicated in the damaging secondary effects of cerebral edema after ischemic and traumatic brain injury, as well as in swelling-related neurodegeneration. CCCs represent attractive therapeutic targets in neurological disorders the pathogenesis of which involves deranged cellular chloride homoestasis.
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PMID:Roles of the cation-chloride cotransporters in neurological disease. 1876 73

Early in postnatal life correlated GABAergic activity in the hippocampus is thought to play a crucial role in synaptogenesis and in the development of adult neuronal networks. Unlike adulthood, at this developmental stage, mossy fibers (MF) which are the axons of granule cells, release GABA into CA3 principal cells and interneurons. Here, we tested the hypothesis that at MF-CA3 connections, tonic activation of GABA(B) autoreceptors by GABA is responsible for the low probability of release and synapse silencing. Blocking GABA(B) receptors with CGP55845 enhanced the probability of GABA release and switched on silent synapses while the opposite was observed with baclofen. Both these effects were presynaptic and were associated with changes in paired-pulse ratio and coefficient of variation. In addition, enhancing the extracellular GABA concentration by repetitive stimulation of MF or by blocking the GABA transporter GAT-1, switched off active synapses, an effect that was prevented by CGP55845. In the presence of CGP55845, stimulation of MF-induced synaptic potentiation. The shift of E(GABA) from the depolarizing to the hyperpolarizing direction with bumetanide, a blocker of the cation-chloride co-transporter NKCC1, prevented synaptic potentiation and caused synaptic depression, suggesting that the depolarizing action of GABA observed in the presence of CGP55845 is responsible for the potentiating effect. It is proposed that, activation of GABA(B) receptors by spillover of GABA from MF terminals reduces the probability of release and contributes to synapses silencing. This would act as a filter to prevent excessive activation of the auto-associative CA3 network and the emergence of seizures.
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PMID:At immature mossy fibers-CA3 connections, activation of presynaptic GABA(B) receptors by endogenously released GABA contributes to synapses silencing. 1927 16

Excitatory GABA action induced by high [Cl(-)](i) is thought to contribute to seizure generation in neonatal neurons although the mechanism of this effect remains unclear. We report that bumetanide, a NKCC1 antagonist, reduces driving force of GABA-mediated currents (DF(GABA)) in neonatal hippocampal neurons and blocks the giant depolarizing potentials (GDPs), a spontaneous pattern of network activity. In the preparation composed of two intact interconnected hippocampi, bumetanide did not prevent generation of kainate-induced seizures, their propagation to the contralateral hippocampus, and formation of an epileptogenic mirror focus. However, in the isolated mirror focus, bumetanide effectively blocked spontaneous epileptiform activity transforming it to the GDP-like activity pattern. Bumetanide partially reduced DF(GABA) and therefore the excitatory action of GABA in epileptic neurons. Therefore bumetanide is a potent anticonvulsive agent although it cannot prevent formation of the epileptogenic mirror focus. We suggest that an additional mechanism other than NKCC1-mediated contributes to the persistent increase of DF(GABA) in epileptic neurons.
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PMID:Bumetanide, an NKCC1 antagonist, does not prevent formation of epileptogenic focus but blocks epileptic focus seizures in immature rat hippocampus. 1929 15

Neonatal seizures have devastating consequences for brain development and are inadequately treated by available antiepileptics. In neonates, gamma-aminobutyric acid (GABA) is an excitatory neurotransmitter due to elevated levels of intraneuronal chloride achieved by robust activity of the Na(+)-K(+)-2Cl( -) cotransporter (NKCC1). This depolarizing action of GABA likely contributes to the lowered seizure threshold, increased seizure propensity, and poor efficacy of GABAergic anticonvulsants among infants. The diuretic bumetanide inhibits NKCC1 and silences seizure activity in rodent models of neonatal seizures, but its effect on seizures in human neonates is unknown. Continuous electroencephalography (EEG) monitoring was used to quantify the number, duration, and frequency of seizures 2 hours before and after the administration of bumetanide in a neonate with intractable multifocal seizures. Significant reductions in mean seizure duration and frequency were noted following treatment, with no associated clinical side effects or metabolic imbalances. These results suggest bumetanide may exert antiepileptic effects in human neonates.
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PMID:Decreased seizure activity in a human neonate treated with bumetanide, an inhibitor of the Na(+)-K(+)-2Cl(-) cotransporter NKCC1. 2153 12

Epileptiform neuronal activity during seizures is observed in many brain areas, but its origins following status epilepticus (SE) are unclear. We have used the Li low-dose pilocarpine rat model of temporal lobe epilepsy to examine early development of epileptiform activity in the deep entorhinal cortex (EC). We show that during the 3-week latent period that follows SE, an increasing percentage of neurons in EC layer 5 respond to a single synaptic stimulus with polysynaptic burst depolarizations. This change is paralleled by a progressive depolarizing shift of the inhibitory postsynaptic potential reversal potential in layer 5 neurons, apparently caused by upregulation of the Cl(-) inward transporter NKCC1 and concurrent downregulation of the Cl(-) outward transporter KCC2, both changes favoring intracellular Cl(-) accumulation. Inhibiting Cl(-) uptake in the latent period restored more negative GABAergic reversal potentials and eliminated polysynaptic bursts. The changes in the Cl(-) transporters were highly specific to the deep EC. They did not occur in layers 1-3, perirhinal cortex, subiculum or dentate gyrus during this period. We propose that the changes in Cl(-) homeostasis facilitate hyperexcitability in the deep entorhinal cortex leading to epileptiform discharge there, which subsequently affects downstream cortical regions.
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PMID:Development of epileptiform excitability in the deep entorhinal cortex after status epilepticus. 1967 83

Electroclinical uncoupling of neonatal seizures refers to electrographic seizure activity that is not clinically manifest. Uncoupling increases after treatment with Phenobarbital, which enhances the GABA(A) receptor (GABA(A)R) conductance. The effects of GABA(A)R activation depend on the intracellular Cl(-) concentration ([Cl(-)](i)) that is determined by the inward Cl(-) transporter NKCC1 and the outward Cl(-) transporter KCC2. Differential maturation of Cl(-) transport observed in cortical versus subcortical regions should alter the efficacy of GABA-mediated inhibition. In perinatal rat pups, most thalamic neurons maintained low [Cl(-)](i) and were inhibited by GABA. Phenobarbital suppressed thalamic seizure activity. Most neocortical neurons maintained higher [Cl(-)](i), and were excited by GABA(A)R activation. Phenobarbital had insignificant anticonvulsant responses in the neocortex until NKCC1 was blocked. Regional differences in the ontogeny of Cl(-) transport may thus explain why seizure activity in the cortex is not suppressed by anticonvulsants that block the transmission of seizure activity through subcortical networks.
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PMID:Differences in cortical versus subcortical GABAergic signaling: a candidate mechanism of electroclinical uncoupling of neonatal seizures. 1975 8

GABA exhibits depolarizing action in the immature neurons due to high intracellular activity of chloride ions. It is maintained by cation-chloride cotransporter NKCC1 which is present in immature brain. Bumetanide is a specific inhibitor of this cotransporter. We studied possible anticonvulsant activity of bumetanide in pentylenetetrazol-induced seizures in three age groups of rat pups (7, 12, and 18 days old). Pretreatment with bumetanide (0.2-1 mg/kg i.p.) resulted in dose-dependent decrease of incidence of the tonic phase of generalized tonic-clonic seizures in 12-day-old rats only. No effect was observed in younger and older animals. Higher dose of bumetanide (2.5 mg/kg) did not affect tonic convulsions but, on the contrary, decreased latencies of generalized seizures in 12-day-old animals. Lack of marked anticonvulsant effect is probably due to relative maturity of neurons in the brainstem where the generator of generalized seizures is localized. Age- and dose-specific suppression of the tonic phase needs further analysis.
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PMID:Age- and dose-specific anticonvulsant action of bumetanide in immature rats. 2005 92

Accumulating evidence suggests that changes in neuronal chloride homeostasis may be involved in the mechanisms by which brain insults induce the development of epilepsy. A variety of brain insults, including status epilepticus (SE), lead to changes in the expression of the cation-chloride cotransporters KCC2 and NKCC1, resulting in intracellular chloride accumulation and reappearance of immature, depolarizing synaptic responses to GABA(A) receptor activation, which may critically contribute to the neuronal hyperexcitability underlying epileptogenesis. In the present study, it was evaluated whether prolonged administration of the selective NKCC1 inhibitor, bumetanide, after a pilocarpine-induced SE modifies the development of epilepsy in adult female rats. The antiepileptic drug phenobarbital, either alone or in combination, was used for comparison. Based on pharmacokinetic studies with bumetanide, which showed extremely rapid elimination and low brain penetration of this drug in rats, bumetanide was administered systemically with different dosing protocols, including continuous intravenous infusion. As shown by immunohistochemistry, neuronal NKCC1 expression was markedly upregulated shortly after SE. Prophylactic treatment with phenobarbital after SE reduced the number of rats developing spontaneous seizures and decreased seizure frequency, indicating a disease-modifying effect. Bumetanide did not exert any significant effects on development of spontaneous seizures nor did it enhance the effects of phenobarbital. However, combined treatment with both drugs counteracted several of the behavioral consequences of SE, which was not observed with single drug treatment. These data do not indicate that bumetanide can prevent epilepsy after SE, but the disease-modifying effect of this drug warrants further studies with more lipophilic prodrugs of bumetanide.
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PMID:Disease-modifying effects of phenobarbital and the NKCC1 inhibitor bumetanide in the pilocarpine model of temporal lobe epilepsy. 2057 6


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