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)

Idiopathic generalized epilepsy (IGE) syndromes are diseases that are characterized by absence, myoclonic, and/or primary generalized tonic-clonic seizures in the absence of structural brain abnormalities. Although it was long hypothesized that IGE had a genetic basis, only recently have causative genes been identified. Here we review mutations in the GABA(A) receptor alpha1, gamma2, and delta subunits that have been associated with different IGE syndromes. These mutations affect GABA(A) receptor gating, expression, and/or trafficking of the receptor to the cell surface, all pathophysiological mechanisms that result in neuronal disinhibition and thus predispose affected patients to seizures.
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PMID:GABA(A) receptor epilepsy mutations. 1717 14

Bipolar disorder is a psychiatric condition characterised by episodes of mania, depression, and underlying mood instability. Anticonvulsant drugs have an established place in the treatment of the disorder, but identifying novel drugs in this class is complicated by the absence of validated animal models. We have evaluated the efficacy of three anticonvulsant mood stabilising drugs (lamotrigine, valproate, and carbamazepine) in a model of mania, in which hyperactivity is induced by the combination of D-amphetamine and chlordiazepoxide. All three drugs were effective at preventing the hyperactivity. Lower doses of valproate and carbamazepine were required to prevent hyperactivity compared to doses required to block tonic-clonic seizures induced by pentylenetetrazole. Lamotrigine was equipotent in the two models. However, the complex pharmacology of the D-amphetamine/chlordiazepoxide model means that there may be several mechanisms by which hyperactivity can be reduced, and these may have more or less relevance to the treatment of bipolar disorder. To address this issue, we also evaluated effects of the three anticonvulsants on baseline locomotion, on activity in the presence of chlordiazepoxide alone, or on activity induced by D-amphetamine alone. Based on the results, we propose that hyperactivity induced by D-amphetamine/chlordiazepoxide may arise through dopaminergic drive coupled with disinhibition caused by low doses of the benzodiazepine. The efficacy of lamotrigine may then arise through a reduction in neuronal excitability or increased glutamate transmission, these latter a consequence of the disinhibition. Carbamazepine may also reduce excitability and glutamate release, but its broader pharmacology, manifested by sedation at higher doses complicates interpretation of its efficacy and reflects its poorer tolerability in the clinic. Valproate may be effective, at least in part, through an enhancement of GABAergic transmission. The predictive validity of the D-amphetamine/chlordiazepoxide model for efficacy in bipolar disorder remains to be established, and research with a wider range of clinically tested drugs is warranted to help validate the model further. In the meantime, the model may be useful for distinguishing novel anticonvulsant drugs with different mechanisms of action.
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PMID:Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania. 1568 Feb

Isolated hypomagnesemia of the idiopathic form is a rare condition that is known to present as generalized motor seizures in children. This report describes a 4-year-old African-American male who presented with a predominant symptom of sudden onset aphasia and no clear initial motor seizure activity. An evaluation revealed an isolated and severe hypomagnesemia (initial serum magnesium levels <1.0 mg/dL) and inappropriate renal handling of magnesium (fractional excretion of magnesium >40% under conditions of hypomagnesemia). The child had subsequent generalized tonic-clonic seizures that were brought under control with valproic acid therapy and magnesium supplementation. Six months after the diagnosis, he had regained 50-60% of his speech and had no further staring spells or motor seizure activity after the initial episode. Isolated and idiopathic hypomagnesemia caused by defective renal reabsorption of magnesium is a rare familial condition with variable inheritance. Aphasia as the solitary presenting symptom has not been described before. The exact pathophysiology of hypomagnesemic aphasia and seizures is not known but may relate to disinhibition of specific types of glutamate receptors. In the present case, neuronal depolarization may have been localized to language areas in the temporal lobes.
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PMID:Isolated idiopathic hypomagnesemia presenting as aphasia and seizures. 1587 16

The question whether general tetanus arises from the independent sum of multiple local tetani or results from the actions of the transynaptic tetanus neurotoxin (TeNT) in higher brain centres remains unresolved. Despite the blood-borne dissemination of TeNT from an infected wound, the access to the central nervous system is probably prevented by the blood-brain barrier. However, several long-term sequelae (e.g. autonomic dysfunction, seizures, myoclonus, and sleep disturbances) present after the subsidence of muscle spasms might be indicative of central actions that occur farther away from lower motoneurons. Subsequently, the obvious entry route is the peripheral neurons followed by the transynaptic passage to the brain. We aimed at describing the pathophysiological correlates of TeNT translocation using the oculomotor system as a comprehensive model of cell connectivity and neuronal firing properties. In this study, we report that injection of TeNT into the medial rectus muscle of one eye resulted in bilateral gaze palsy attributed to firing alterations found in the contralaterally projecting abducens internuclear neurons. Functional alterations in the abducens-to-oculomotor internuclear pathway resembled in part the classically described TeNT disinhibition. We confirmed the transynaptic targeted action of TeNT by analysing vesicle-associated membrane protein2 (VAMP2) immunoreactivity (the SNARE protein cleaved by TeNT). VAMP2 immunoreactivity decreased by 94.4% in the oculomotor nucleus (the first synaptic relay) and by 62.1% presynaptic to abducens neurons (the second synaptic relay). These results are the first demonstration of physiological changes in chains of connected neurons that are best explained by the transynaptic action of TeNT on premotor neurons as shown with VAMP2 immunoreactivity which serves as an indicator of TeNT activity.
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PMID:Transynaptic effects of tetanus neurotoxin in the oculomotor system. 1598 57

In addition to its potent effects on vasculature, it has become clear that vascular endothelial growth factor (VEGF) has effects on both neurons and glia, and recent studies suggest that it can be neuroprotective. To determine potential mechanisms underlying this neuroprotection, recombinant human VEGF was bath applied to adult rat hippocampal slices, and both extracellular and intracellular recordings were used to examine intrinsic properties and synaptic responses of hippocampal principal neurons. Initial studies in area CA1 showed that VEGF significantly reduced the amplitude of responses elicited by Schaffer collateral stimulation, without influencing membrane properties. Similar effects occurred in CA3 pyramidal cells and dentate gyrus granule cells when their major glutamatergic afferents were stimulated. Because VEGF expression is increased after seizures, effects of VEGF were also examined in rats with recurrent spontaneous seizures. VEGF reduced spontaneous discharges in slices from these rats but had surprisingly little effect on epileptiform discharges produced by disinhibition of slices from control rats. These results demonstrate a previously unknown effect of VEGF on neuronal activity and also demonstrate a remarkable potency in the epileptic brain. Based on this, we suggest that VEGF or VEGF-related targets could provide useful endpoints to direct novel therapeutic strategies for epilepsy.
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PMID:Depression of synaptic transmission by vascular endothelial growth factor in adult rat hippocampus and evidence for increased efficacy after chronic seizures. 1619 78

Most human idiopathic generalized epilepsies (IGEs) are polygenic, but virtually nothing is known of the molecular basis for any of the complex epilepsies. Recently, two GABAA receptor delta subunit variants (E177A, R220H) were proposed as susceptibility alleles for generalized epilepsy with febrile seizures plus and juvenile myoclonic epilepsy. In human embryonic kidney 293T cells, recombinant halpha1beta2delta(E177A) and halpha1beta2delta(R220H) receptor currents were reduced, but the basis for the current reduction was not determined. We examined the mechanistic basis for the current reduction produced by these variants using the halpha4beta2delta receptor, an isoform more physiologically relevant and linked to epileptogenesis, by characterizing the effects of these variants on receptor cell surface expression and single-channel gating properties. Expression of variant alpha4beta2delta(R220H) receptors resulted in a decrease in surface receptor proteins, and a smaller, but significant, reduction was observed for variant alpha4beta2delta(E177A) receptors. For both variants, no significant alterations of surface expression were observed for mixed population of wild-type and variant receptors. The mean open durations of alpha4beta2delta(E177A) and alpha4beta2delta(R220H) receptor single-channel currents were both significantly decreased compared to wild-type receptors. These data suggest that both delta(E177A) and delta(R220H) variants may result in disinhibition in IGEs by similar cellular and molecular mechanisms, and in heterozygously affected individuals, a reduction in channel open duration of delta subunit-containing GABAA receptors may be the major contributor to the epilepsy phenotypes.
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PMID:Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors. 1645 73

We investigated the dependency of electrical seizures produced by cortical undercut upon behavioral states of vigilance in chronically implanted cats. Experiments were performed 1-12 weeks after white matter transection. Multisite field potentials and intracellular activity were recorded from suprasylvian and marginal gyri. Paroxysmal activity developed within days and consisted of spike-wave complexes at 3-4 Hz occurring during the waking state (correlated with eye movements), being enhanced during slow-wave sleep (SWS) and blocked during rapid eye movement (REM) sleep. Prolonged hyperpolarizing events were seen not only during SWS (which is the case in normal animals) but also during both waking and REM, thus resulting in bimodal distribution of the membrane potential in all 3 natural states of vigilance. The increased synchrony of field potential activity expressed by shorter time of propagation over the cortical surface and the tendency toward generalization are ascribed to changes in intrinsic neuronal properties and potential disinhibition following cortical undercut.
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PMID:Waking-sleep modulation of paroxysmal activities induced by partial cortical deafferentation. 1649 31

Clinicians use the word disinhibition and its derivatives to describe a resident's behavior. Up to 30% of people with dementia may manifest behavioral disinhibition; sexual disinhibition is also a problem, but less frequently. Several causal relationships have been hypothesized, with frontal lobe deterioration among the best documented. Lobar lesions or trauma, seizure activity, cerebellar dysfunction, and drugs have been implicated as well. Behavioral disinhibition creates clinical challenges in the long-term care facility, and to date, no drug treatment has been approved for this indication. Behavioral interventions are the strategies of first choice. Reports of drug treatment are limited to case reports and very small studies.
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PMID:Disinhibition: clinical challenges in the long-term care facility. 1654 75

Rodents use rhythmic vibrissae movements to sense the environment. It is currently unclear whether intrinsic activity in the vibrissa motor cortex (vMI) is capable of driving vibrissa movements on a cycle-by-cycle basis. Disinhibition of vMI results in the occurrence of spontaneous 5- to 15-Hz synchronized oscillations. In behaving rats, this synchronous resonance of vMI is shown here to drive contralateral vibrissa movements that are phase-locked to each cycle of the oscillation. In contrast to active whisking during sensing, which consists of active protractions, the vibrissa movements produced by vMI oscillations consisted of rhythmic retractions. The results demonstrate that rhythmic motor cortex output is capable of driving vibrissa movements on a cycle-by-cycle basis. Such motor output may be primarily expressed during abnormal states such as those related to cortical myoclonous, tremors, and cortical seizures.
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PMID:Vibrissa myoclonus (rhythmic retractions) driven by resonance of excitatory networks in motor cortex. 1680 44

The piriform cortex makes strong interconnections with limbic structures (amygdala, entorhinal cortex and hippocampus) that are involved in memory processing. These connections have also been implicated in the development of temporal lobe epilepsy. However, little is known about how neurones in this region may change during seizure genesis. Here we tested the hypothesis that in the kindling model of temporal lobe epilepsy GABAA receptor-mediated inhibition is altered in the piriform cortex. To do this we performed whole-cell patch-clamp recordings in piriform cortex brain slices obtained from non-kindled and amygdala-kindled adult rats. We found that kindling coincided with an increase in the amplitude and duration of miniature inhibitory post-synaptic currents (mIPSCs) recorded from non-pyramidal neurones, whereas the mIPSCs occurring on pyramidal (excitatory) cells did not change. Non-stationary noise analysis of mIPSCs occurring on the non-pyramidal neurones showed that inferred unitary conductance of synaptic channels were the same before and after kindling, implying that the channel number increased significantly. Immunocytochemical analysis of the inhibitory innervation showed that it was also unaltered by seizure induction. We also found that the effect of the positive modulator tetrahydrodeoxycorticosterone was reduced on the pyramidal neurones after kindling. In contrast, the potentiating effects of tetrahydrodeoxycorticosterone on non-pyramidal cells were about the same after kindling as in control (sham) rats. These data indicate that amygdala kindling causes a shift in the inhibition 'balance' between the pyramidal and non-pyramidal cells, perhaps leading to the disinhibition of pyramidal cells.
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PMID:Kindling-induced alterations in GABAA receptor-mediated inhibition and neurosteroid activity in the rat piriform cortex. 1698 22


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