1,721,022 research outputs found
Neuronal nicotinic receptors and nocturnal frontal lobe epilepsy.
No full textCarbamazepine (5H-dibenz[b,f]azepine-5-carboxamide) and oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) are widely used for the treatment of partial epilepsy. Recent work indicates that these drugs, in addition to targeting voltage-gated Na(+) channels, can modulate ligand-gated channels. These compounds appear to be particularly effective for treatment of nocturnal frontal lobe epilepsy, which can be caused by mutant neuronal nicotinic receptors. We compared the effects of carbamazepine and oxcarbazepine on heteromeric nicotinic receptors to better understand the underlying mechanism of the effect of these drugs in epileptic patients. Receptors were expressed in cell lines and studied by patch-clamp methods at -60 mV. For alpha2beta4 receptors activated with 100 microM nicotine, IC(50) for carbamazepine was 49 microM. Receptors in which alpha2 was substituted with alpha2-I279 N, linked to autosomal dominant nocturnal frontal lobe epilepsy, had an IC(50) of 21 microM. For oxcarbazepine, the IC(50) was larger than 500 microM for wild-type receptors and approximately 100 microM for mutant receptors. A similar inhibition was observed in the presence of 10 microM nicotine, indicating a non-competitive mechanism. The monohydroxy derivative (MHD) of oxcarbazepine, clinically the most relevant compound, was tested on both alpha2beta4 and alpha4beta2 receptors, to obtain a broader view of its possible physiological effects. At the typical concentration present in blood (100 microM), MHD produced an approximate 40% channel block on alpha4beta2, but no significant effect on alpha2beta4 receptors. Oxcarbazepine and MHD retarded the channel deactivation, suggesting that these compounds produce open channel block. These results may explain the particular efficacy of these drugs in nocturnal frontal lobe epilepsy
Altered GABA signalling in a mouse model of fragile X syndrome.
No full textThe absence of fragile X mental retardation protein results in the fragile X syndrome (FXS), a common form of mental retardation associated with attention deficit, autistic behavior, and epileptic seizures. The phenotype of FXS is reproduced in fragile X mental retardation 1 (fmr1) knockout (KO) mice that have region-specific altered expression of some gamma-aminobutyric acid (GABA(A)) receptor subunits. However, little is known about the characteristics of GABAergic inhibition in the subiculum of these animals. We employed patch-clamp recordings from subicular pyramidal cells in an in vitro slice preparation. In addition, semiquantitative polymerase chain reaction and western blot experiments were performed on subiculum obtained from wild-type (WT) and KO mice. We found that tonic GABA(A) currents were downregulated in fmr1 KO compared with WT neurons, whereas no significant differences were observed in phasic GABA(A) currents. Molecular biology analysis revealed that the tonic GABA(A) receptor subunits alpha5 and delta were underexpressed in the fmr1 KO mouse subiculum compared with WT. Because the subiculum plays a role in both cognitive functions and epileptic disorders, we propose that altered tonic inhibition in this structure contributes to the behavioral deficits and epileptic activity seen in FXS patients. This conclusion is in line with evidence implicating tonic GABA(A) inhibition in learning and memory
The role of seizures in the early stages of Alzheimer’s disease.
No full textEpilepsy in Alzheimer Disease animal model and prevention of seizure by AED administration reduces cognitive deficits (compared to alzheimer animals with seizures untreated with AED
Nicotinic acetylcholine receptors and nocturnal frontal lobe epilepsy
No full textSleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. We identified a new genetic locus for familial sleep-related focal epilepsy on chromosome 8p12.3-8q12.3. By sequencing the positional candidate neuronal cholinergic receptor alpha 2 subunit gene (CHRNA2), we detected a heterozygous missense mutation, I279N, in the first transmembrane domain that is crucial for receptor function. Whole-cell recordings of transiently transfected HEK293 cells expressing either the mutant or the wild-type receptor showed that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine, therefore indicating that the nicotinic alpha 2 subunit alteration is the underlying cause. CHRNA2 is the third neuronal cholinergic receptor gene to be associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior
Modulating effect of PKC-dependent channel phosphorylation on sodium current inhibition operated by the antiepileptic drug topiramate.
No full textBACKGROUND AND PURPOSE:
Topiramate is a novel anticonvulsant known to modulate the activity of several ligand- and voltage-gated ion channels in neurons. The mechanism of action of topiramate, at a molecular level, is still unclear, but the phosphorylation state of the channel/receptor seems to be a factor that is able to influence its activity. We investigated the consequences of phosphorylation of the sodium channel on the effect of topiramate on tetrodotoxin (TTX)-sensitive transient Na(+) current (I(NaT)).
EXPERIMENTAL APPROACH:
I(NaT) was recorded in dissociated neurons of rat sensorimotor cortex using whole-cell patch-clamp configuration.
KEY RESULTS:
We found that topiramate (100 microM) significantly shifted the steady-state I(NaT) inactivation curve in a hyperpolarized direction. In neurons pre-treated with a PKC-activator, 1-oleoyl-2-acetyl-sn-glycerol (OAG; 2 microM), the net effect of topiramate on steady-state I(NaT) inactivation was significantly decreased. In addition, OAG also slightly shifted the I(NaT) activation curve in a hyperpolarized direction, while perfusion with topiramate had no effect on the parameters of I(NaT) activation.
CONCLUSIONS AND IMPLICATIONS:
These data show that PKC-activation can modulate the effect of topiramate on I(NaT). This suggests that channel phosphorylation in physiological or pathological conditions (such as epiliepsy), can alter the action of topiramate on sodium currents
Insular excitability and characterisation of the effect of GluR5 receptors in a rodent model of temporal lobe epilepsy
No full textThe insular cortex (IC) is involved in the generalization of epileptic discharges in temporal lobe epilepsy (TLE), whereas seizures originating in the IC can mimic the epileptic phenotype seen in some patients with TLE. However, few studies have addressed the changes occurring in the IC in TLE animal models. Here, we analyzed the immunohistochemical and electrophysiological properties of IC networks in non-epileptic control and pilocarpine-treated epileptic rats. Neurons identified with a neuron-specific nuclear protein antibody showed similar counts in the two types of tissue but parvalbumin- and neuropeptide Y-positive interneurons were significantly decreased (parvalbumin, approximately -35%; neuropeptide Y, approximately -38%; P < 0.01) in the epileptic IC. Non-adapting neurons were seen more frequently in the epileptic IC during intracellular injection of depolarizing current pulses. In addition, single-shock electrical stimuli elicited network-driven epileptiform responses in 87% of epileptic and 22% of non-epileptic control neurons (P < 0.01) but spontaneous postsynaptic potentials had similar amplitude, duration and intervals of occurrence in the two groups. Finally, pharmacologically isolated, GABA(A) receptor-mediated inhibitory postsynaptic potentials had more negative reversal potential (P < 0.01) and higher peak conductance (P < 0.05) in epileptic tissue. These data reveal moderate increased network excitability in the IC of pilocarpine-treated epileptic rats. We propose that this limited degree of hyperexcitability originates from the loss of parvalbumin- and neuropeptide Y-positive interneurons that is compensated by an increased drive for GABA(A) receptor-mediated inhibition
Increased perivascular laminin predicts damage to astrocytes in CA3 and piriform cortex following chemoconvulsive treatments
No full textStatus epilepticus (SE) induced by pilocarpine or kainate is associated with yet notsystemically investigated astrocytic and vascular injuries. To investigate their possibleassociation with neuronal damage, the changes in glial fibrillary acidic protein (GFAP),laminin and neuron-specific nuclear protein (NeuN) immunoreactivities were analyzed in ratstreated with pilocarpine (380 mg/kg) or kainate (15 mg/kg), and receiving diazepam (20mg/kg) after 10 min of SE. A different group of rats was injected with endothelin-1 (ET-1) inthe caudate putamen to reproduce the changes in GFAP and laminin immunoreactivitiesassociated with ischemia. Focal loss of GFAP immunostaining was accompanied byincreased laminin immunoreactivity in blood vessels, in all the examined groups. Regressionanalysis revealed a significant (P < 0.01) relationship between astrocytic lesion andincreased laminin immunoreactivity in the piriform cortex (Pir) of both pilocarpine (R2 = 0.88)and kainate (R2 = 0.94) groups of treatment. A significant relationship (P < 0.01; R2 = 0.81)was also present in the CA3 hippocampal region of pilocarpine-treated rats. At variance,neuronal and glial lesions were significantly related (P < 0.05, R2 = 0.74) only in thesubstantia nigra of pilocarpine-treated rats. The ratio between areas of GFAP and lamininchanges of immunoreactivity in the ET-1 group was similar to those found in pilocarpineandkainate-treated rats in specific brain regions, such as the hippocampal CA3 subfield, Pirand the anterior olfactory nucleus. The amygdala and submedius thalamic nucleus in thepilocarpine group, and the perirhinal and entorhinal cortices in the kainate group, alsopresented ischemic-like changes. These results indicate that laminin immunoreactivity isupregulated in the basal lamina of blood vessels after SE induced by pilocarpine or kainate.This phenomenon is significantly associated with lesions involving more glial than neuronalcells, in specific cerebral regions
Audiogenic seizures selectively activate hippocampal neurons in young mice affected by fragile X syndrome
No full textYoung, but not adult, fragile X mental retardation gene (Fmr1) knockout (KO) mice display audiogenic seizures (AGS) that can be prevented by inhibiting extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation. In order to identify the cerebral regions involved in these phenomena, we characterized the response to AGS in Fmr1 KO mice and wild type (WT) controls at postnatal day (P) 45 and P90. To characterize the diverse response to AGS in various cerebral regions, we evaluated the activity markers FosB/ΔFosB and phosphorylated ERK1/2 (p-ERK1/2). Wild running (100% of tested mice) followed by clonic/tonic seizures (30%) were observed in P45 Fmr1 KO mice, but not in WT mice. In P90 Fmr1 KO mice, wild running was only present in 25% of tested animals. Basal FosB/ΔFosB immunoreactivity was higher (P < 0.01 vs. WT) in the CA1 and subiculum of P45 Fmr1 KO mice. Following the AGS test, FosB/ΔFosB expression consistently increased in most of the analyzed regions in both groups at P45, but not at P90. Interestingly, FosB/ΔFosB immunoreactivity was significantly higher in P45 Fmr1 KO mice in the medial geniculate body (P < 0.05 vs. WT) and CA3 (P < 0.01). Neurons presenting with immunopositivity to p-ERK1/2 were more abundant in the subiculum of Fmr1 KO mice in control condition (P < 0.05 vs. WT, in both age groups). In this region, p-ERK1/2-immunopositive cells significantly decreased (-75%, P < 0.01) in P90 Fmr1 KO mice exposed to the AGS test, but no changes were found in P45 mice or in other brain regions. In both age groups of WT mice, p-ERK1/2-immunopositive cells increased in the subiculum after exposure to the acoustic test. Our findings illustrate that FosB/ΔFosB markers are overexpressed in the medial geniculate body and CA3 in Fmr1 KO mice experiencing AGS, and that p-ERK1/2 is markedly decreased in the subiculum of Fmr1 KO mice resistant to AGS induction. These findings suggest that resilience to AGS is associated with dephosphorylation of p-ERK1/2 in the subiculum of mature Fmr1 KO mice
Downregulation of tonic GABAA receptor-mediated inhibition in a mouse model of Fragile X syndrome
No full textThe absence of fragile X mental retardation protein results in the fragile X syndrome (FXS), a common form of mental retardation associated with attention deficit, autistic behavior, and epileptic seizures. The phenotype of FXS is reproduced in fragile X mental retardation 1 (fmr1) knockout (KO) mice that have region-specific altered expression of some gamma-aminobutyric acid (GABA(A)) receptor subunits. However, little is known about the characteristics of GABAergic inhibition in the subiculum of these animals. We employed patch-clamp recordings from subicular pyramidal cells in an in vitro slice preparation. In addition, semiquantitative polymerase chain reaction and western blot experiments were performed on subiculum obtained from wild-type (WT) and KO mice. We found that tonic GABA(A) currents were downregulated in fmr1 KO compared with WT neurons, whereas no significant differences were observed in phasic GABA(A) currents. Molecular biology analysis revealed that the tonic GABA(A) receptor subunits alpha5 and delta were underexpressed in the fmr1 KO mouse subiculum compared with WT. Because the subiculum plays a role in both cognitive functions and epileptic disorders, we propose that altered tonic inhibition in this structure contributes to the behavioral deficits and epileptic activity seen in FXS patients. This conclusion is in line with evidence implicating tonic GABA(A) inhibition in learning and memory
Electrocorticography demonstrates beneficial effects of EP-80317 in a model of status epilepticus
No full textStatus epilepticus (SE) is a serious life-threatening condition. Treatment of SE is based on a stage approach, going from benzodiazepines in the early stage to intensive care unit and general anesthesia in severe stages. Treatment of SE is frequently unsuccessful, and high levels of mortality and morbidity are reported. Several risk factors for SE occurrence and recurrence have been identified, making prevention of this condition a primary objective. EP-80317, a ghrelin receptor antagonist, displays anticonvulsant properties on behavioral convulsive episodes. In this study, we have characterized the ability of EP-80317 to prevent progression from non-convulsive to convulsive seizures and to SE in the pilocarpine model by video-electrocorticography. SE developed in 100% of rats pretreated with saline, but only in 50% of those pretreated with EP-80317. Seizures were similarly evoked in both groups, but different rates of convulsive vs. non-convulsive episodes were observed. In particular, the rate of convulsive seizures was 15% in EP-80317-pretreated rats that did not experience SE (EP-80317/Non-SE), whereas it was about 75% in saline-pretreated group and in EP-80317-pretreated rats that experienced SE (EP-80317/SE). Moreover, after pilocarpine administration, saline-pretreated and EP-80317/SE rats showed a worsening in behavioral manifestation and seizure duration, and a progression of the power spectrum of convulsive seizures. This progressive worsening was not observed in EP-80317/Non-SE rats. We report for the first time that EP-80317 prevents the progression from non-convulsive to convulsive seizures and to SE in pilocarpine-treated rats
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