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)

We report an early infantile patient characterized by intractable hyponatremia, progressive megalencephaly, and epileptic seizures with an EEG pattern that alternated between interictal low-voltage background and ictal burst activity. Repeatedly all the abnormal findings improved in a lidocaine-dependent manner. Given the pharmacologic mechanisms of lidocaine as a sodium channel blocker, we speculate that our patient had a sodium channel dysfunction.
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PMID:Lidocaine-dependent early infantile status epilepticus with highly suppressed EEG. 1190 70

Seizurogenic activity develops in many patients following brain injury and may be involved in the pathophysiological effects of brain trauma and stroke. We have evaluated the effects of the use-dependent sodium channel blocker RS100642, an analog of mexiletine, as a neuroprotectant and anti-seizure agent in a rat model of transient middle cerebral artery occlusion (MCAo). Post-injury treatment with RS100642 (0.01-5.0 mg/kg) dose-dependently reduced brain infarction, improved functional recovery of electroencephalographic (EEG) power, and improved neurological outcome following 2 h of MCAo and 24 h recovery. This effect was more potent and offered a larger reduction of brain infarct volume than a maximal neuroprotective dose of mexiletine (10.0 mg/kg). Furthermore, brain seizure activity recorded following 1 h MCAo and 72 h of recovery in injured rats was either completely blocked (30 min pre-MCAo treatment) or significantly reduced (30 min post-MCAo treatment) with RS100642 (1.0 mg/kg) treatment resulting in greater than 60% reduction of core brain infarct. These results indicate that brain seizure activity during MCAo likely contributes to the pathophysiology of brain injury and that RS100642 may be an effective neuroprotective treatment not only to decrease brain injury but also to reduce the pathological EEG associated with focal ischemia.
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PMID:Neuroprotective effects of the sodium channel blocker RS100642 and attenuation of ischemia-induced brain seizures in the rat. 1191 60

Hypomagnesemia has previously been recognized as an uncommon cause of seizures. The electrolyte abnormality is caused by poor gastrointestinal absorption or excessive renal wasting, both from a variety of causes. We report on a 5-week-old patient who developed hypomagnesemic seizures as a consequence of renal magnesium wasting. Although the exact pathophysiology of hypomagnesemic seizures remains uncertain, currently available information suggests that it is related to disinhibition of the N-methyl-D-aspartate-type glutamate receptor-sodium channel complex.
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PMID:Hypomagnesemic seizures: case report and presumed pathophysiology. 1191 75

Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected individuals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome.
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PMID:Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. 1201 Dec 99

Intracellular and extracellular pH are known to influence neuronal activity and may play a role in seizure termination. In the pyramidal cell layer of the CA1 region of the hippocampus in the urethane anesthetized adult rat, there is an initial alkalinization in response to stimulus trains administered to the contralateral CA3 region. This is followed by an acidification that peaks after termination of the afterdischarge. Initial experiments demonstrated that the peak level of acidification correlated with the duration of the afterdischarge, but that the peak level of alkalinization did not. The effects of several antiepileptic drugs on the initial alkalinization were determined. Systemic administration of acetazolamide (50 mg/kg, n=4) and topiramate (45 mg/kg, n=7) and local administration of benzolamide (n=3), all of which inhibit carbonic anhydrase, decreased the initial alkalinization that occurs during the stimulus train. Diazepam (3 mg/kg, n=5) and phenobarbital (60 mg/kg, n=6), agonists at the GABA(A) receptor complex, increased the initial alkalinization, while sodium channel blockers phenytoin (80 mg/kg, n=5) and carbamazepine (50 mg/kg, n=5) had no significant effect. The data suggest that the alkalinization in CA1 in vivo is predominantly regulated through activity of the GABA(A) receptor, rather than through activation of glutamatergic receptors. The change in alkalinization does not appear to be related to the mechanism of the antiepileptic effect of the drugs that were tested.
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PMID:Effects of antiepileptic drugs on extracellular pH regulation in the hippocampal CA1 region in vivo. 1204 2

The anticonvulsant properties of the ss-adrenoceptor antagonist propranolol and its two enantiomers were examined in various screening tests in order to characterize the anticonvulsant profile as well as the possible molecular mechanism of action. These compounds dose-dependently raised the threshold for tonic electroshock seizures in mice and were effective in the traditional maximal electroshock test (ED (50)s 15- 20 mg kg (-1)i.p.). In combination with clinically used antiepileptics, the anticonvulsant effectiveness of the latter was significantly increased. In the pentylenetetrazol (85 mg kg (-1)s.c.) seizure threshold test, ( +/-)- and ( +)-propranolol were not effective in preventing clonic seizures. In unrestrained rats with chronically implanted electrodes in the dorsal hippocampus, propranolol and its ( +)-enantiomer equieffectively reduced the duration of electrically-evoked hippocampal afterdischarges (10 and 20 mg kg (-1)i.p.) and raised the focal stimulation threshold (20 mg kg (-1)i.p.). In amygdala-kindled rats, both drugs ( >or= 10 mg kg (-1)i.p.) reduced the seizure severity from stage 5 (generalized clonic-tonic) to stage 3 (unilateral forelimb) seizures. Furthermore, whole-cell patch-clamp experiments showed that ( +)- as well as ( -)-propranolol ( 10(-6)to 10(-4)M) depressed the fast inward sodium current in a concentration- and use-dependent manner in cultured rat cardiomyocytes and inhibited picrotoxin-induced burst firing activity of mouse spinal cord neurones in culture. In conclusion, propranolol and its two enantiomers have anticonvulsant effects in models for generalized tonic-clonic and complex partial seizures which may be accounted for by the sodium channel blocking and not by the ss-adrenoceptor blocking activity.
Seizure 2002 Jul
PMID:Anticonvulsant profile and mechanism of action of propranolol and its two enantiomers. 1207 1

The persistent, slowly inactivating fraction of the sodium current is involved in key functions in the CNS such as dendritic integration of synaptic inputs and cellular excitability. We have studied whether established anti-epileptic drugs and neuroprotective agents target the persistent sodium current. Two lamotrigine derivatives (sipatrigine and 202W92) and riluzole inhibited the persistent sodium current at low, therapeutic concentrations. In contrast, lamotrigine and the classical antiepileptic agents phenytoin and valproic acid blocked the fast-inactivating sodium channel but failed to affect the persistent fraction. The ability to influence either mode of channel activity may represent a defining feature of each drug subclass, changing profoundly their clinical indications. Given the damaging role of a sustained influx of sodium in both pharmaco-resistant seizures or excitotoxic insults, we suggest the utilization of drugs that suppress the persistent conductance.
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PMID:Lamotrigine derivatives and riluzole inhibit INa,P in cortical neurons. 1215 62

Sodium channel beta-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated beta2(-/-) mice to investigate the role of beta2 in control of sodium channel density, localization, and function in neurons in vivo. Measurements of [(3)H]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in beta2(-/-) neurons. The loss of beta2 resulted in negative shifts in the voltage dependence of inactivation as well as significant decreases in sodium current density in acutely dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was significantly reduced, and the threshold for action potential generation was increased, indicating a reduction in the level of functional plasma membrane sodium channels. In contrast, the conduction velocity, the number and size of axons in the optic nerve, and the specific localization of Na(v)1.6 channels in the nodes of Ranvier were unchanged. beta2(-/-) mice displayed increased susceptibility to seizures, as indicated by reduced latency and threshold for pilocarpine-induced seizures, but seemed normal in other neurological tests. Our observations show that beta2-subunits play an important role in the regulation of sodium channel density and function in neurons in vivo and are required for normal action potential generation and control of excitability.
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PMID:Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits. 1248 Oct 39

Generalized epilepsy with febrile seizures plus type 1 is an inherited human epileptic syndrome, associated with a cysteine-to-tryptophan (C121W) mutation in the extracellular immunoglobin domain of the auxiliary beta1 subunit of the voltage-gated sodium channel. The mutation disrupts beta1 function, but how this leads to epilepsy is not understood. In this study, we make several observations that may be relevant for understanding why this beta1 mutation results in seizures. First, using electrophysiological recordings from mammalian cell lines, coexpressing sodium channel alpha subunits and either wild-type beta1 or C121Wbeta1, we show that loss of beta1 functional modulation, caused by the C121W mutation, leads to increased sodium channel availability at hyperpolarized membrane potentials and reduced sodium channel rundown during high-frequency channel activity, compared with channels coexpressed with wild-type beta1. In contrast, neither wild-type beta1 nor C121Wbeta1 significantly affected sodium current time course or the voltage dependence of channel activation. We also show, using a Drosophila S2 cell adhesion assay, that the C121W mutation disrupts beta1-beta1 homophilic cell adhesion, suggesting that the mutation may alter the ability of beta1 to mediate protein-protein interactions critical for sodium channel localization. Finally, we demonstrate that neither functional modulation nor cell adhesion mediated by wild-type beta1 is occluded by coexpression of C121Wbeta1, arguing against the idea that the mutant beta1 acts as a dominant-negative subunit. Together, these data suggest that C121Wbeta1 causes subtle effects on channel function and subcellular distribution that bias neurons toward hyperexcitabity and epileptogenesis.
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PMID:Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1. 1248 63

Nine mutations that cause generalized epilepsy with febrile seizures plus have been identified in the SCN1A gene encoding the alpha subunit of the Na(v)1.1 voltage-gated sodium channel. The functional properties of two of these mutations (T875M and R1648H) have previously been described. T875M was shown to enhance slow inactivation, while R1648H dramatically accelerated recovery from inactivation. In this report, we have cloned, expressed and characterized the functional effects of a third generalized epilepsy with febrile seizures plus mutation, W1204R (Am J Hum Genet 68 (2001) 866). The mutation was cloned into the orthologous rat channel, rNa(v)1.1, and at the same time a single base pair insertion at base 120 in the original rNa(v)1.1 clone was corrected. The level of expression of the corrected wild-type rNa(v)1.1 was approximately 1000-fold higher than that of the original clone and comparable to that achieved with other neuronal sodium channels expressed in Xenopus oocytes. The properties of the W1204R mutant in the corrected rNa(v)1.1 were determined in the absence and presence of the beta1 subunit in Xenopus oocytes. The W1204R mutation resulted in approximately 11 mV hyperpolarized shifts in the voltage-dependence of activation and steady-state inactivation when expressed as an alpha subunit alone. When the channels were coexpressed with the beta1 subunit, the hyperpolarized shifts were still present but smaller, approximately 5 mV in magnitude. All other properties that we examined were comparable for the mutant and wild-type channels. The negative shift in activation would increase channel excitability, whereas the negative shift in inactivation would decrease excitability. The negative shifts in both properties also shifted the window current, which is the voltage region in which sodium channels can continue to open because some percentage of channels are activated and not all of the channels are inactivated. The shift in window current for the W1204R mutation could result in hyperexcitability because the neuron's potential is more likely to reach the more negative range. These results demonstrate that a third SCN1A mutation that causes generalized epilepsy with febrile seizures plus 2 alters the properties of the sodium channel in a different manner than the previous two mutations that were studied. The diversity in functional effects for these three mutations indicates that a similar clinical phenotype can result from very different underlying sodium channel abnormalities.
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PMID:Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Na(v)1.1 sodium channels. 1253 36


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