Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The author reviews European studies on the effect of the anticonvulsant agent valproate in the treatment of bipolar affective disorder. Since mania is associated with depletion of inhibitory transmitters in the central nervous system and gamma-aminobutyric acid (GABA) is one of the most important inhibitory transmitters, the GABAergic effects of valproate provide a theoretical basis for its use in affective disorders. The European studies, which have been both open and controlled, showed beneficial effects of valproate in acute and prophylactic treatment of bipolar illness, with particularly good results in mania. Side effects reported most often were mild and transient, and included gastrointestinal upset, lethargy, increased levels of hepatic transaminases, and mild alopecia.
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PMID:Valproate use in acute mania and bipolar disorder: an international perspective. 249 52

The most important recent development in primary generalized epilepsy has been the use of in-vitro and in-vivo models to delineate the neuronal populations and intrinsic mechanisms, which generate the synchronized thalamocortical burst-firing of absence seizures. Candidate molecular mechanisms, which may be critically involved in the pathogenesis of absence seizures in selected animal models, include the following: altered biophysical properties of T-type calcium channels in the genetic absence epilepsy rat of Strasbourg (GAERS) model; increased numbers of gamma-aminobutyric acid, B subtype receptors in the lethargic mouse (lh/lh mouse) model; and changes in the subunit composition of gamma-aminobutyric acid, A subtype receptors in the GAERS model. Regarding generalized convulsive seizures, neuronal populations within the inferior and superior colliculi appear to regulate seizures in the genetic epilepsy-prone rat (GEPR) model, and subpopulations within the substantia nigra pars reticulata (SNR) appear to regulate seizures in the fluorothyl model. Deficiencies in the function of GABAergic and noradrenergic receptors may underlie generalized convulsive seizures in the GEPR model.
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PMID:Models of primary generalized epilepsy. 762 May 85

Ethanol withdrawal (ETX) in ethanol-dependent rats results in susceptibility to seizures, including generalized tonic-clonic audiogenic seizures (AGS). The inferior colliculus (IC) is strongly implicated in AGS initiation during ETX, but IC neuronal mechanisms subserving AGS are unclear. The present study examined IC (central nucleus) single neuronal firing during repeated (4 day) intragastric ethanol administration and during ETX. This involved microwire electrodes implanted chronically into freely moving rats and acoustic stimulation in intensities up to 105 dB SPL. During initial ethanol administration the animals were stuporous, and IC spontaneous neuronal firing and acoustically evoked firing at high stimulus intensities were significantly reduced. This firing reduction is consistent with the action of ethanol to enhance gamma-aminobutyric acid (GABA)-mediated inhibition, which is prominent in IC neurons at high stimulus intensities. During ETX the animals were agitated, and spontaneous IC neuronal firing and acoustically evoked firing at all stimulus intensities were significantly increased during the period of AGS susceptibility. Previous studies indicate that IC neuronal responses are tightly regulated by GABA and glutamate. The IC firing increases during ETX in the present study may involve the down-regulation of GABAA receptors and supersensitivity of glutamate receptors reported to occur during ETX. Previous studies also indicate that focal blockade of GABAA receptors or activation of glutamate receptors produces AGS susceptibility in normal rats. Therefore, the IC neuronal firing increases observed in the present study may play a critical role in initiation of AGS during ethanol withdrawal.
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PMID:Ethanol withdrawal induces increased firing in inferior colliculus neurons associated with audiogenic seizure susceptibility. 772 Aug 30

Classical Maple Syrup Urine Disease (MSUD) is a disease of infancy which is an inherited disorder of metabolism of branched-chain amino acids (BCAA). The BCAA are normally transaminated to branched-chain keto acids (BCKA). However, the enzyme required to metabolize the BCKA is deficient, resulting in elevation of both, the BCAA and the BCKA. One of the BCAA (isoleucine) produces a metabolite that causes the urine to smell like maple syrup. The elevations of the BCAA and BCKA are associated with an acute, critical neurotoxic condition often prior to the age of two weeks. The clinical state, the electroencephalogram-(EEG), and plasma BCAA levels were evaluated in 26 patients with classical and variant MSUD. Patients were seen from the time of diagnosis, often within a week after birth, and some were followed clinically for more than 20 years while on specific diet therapy. They were monitored by plasma BCAA (leucine, isoleucine and valine) levels and a total of 101 EEGs were performed during different phases of their illness. During periods of acute metabolic decompensation, there were marked clinical symptoms of neurotoxicity including opisthotonos, seizures, and coma with elevated BCAA plasma levels. The EEGs revealed spikes, polyspikes, spike-wave complexes, triphasic waves, severe slowing and bursts of periodic suppression. Occasionally paradoxical EEG arousal was noted while the patient was lethargic. During asymptomatic periods when the plasma BCAA were at low or normal levels, EEG abnormalities occurred in patients with and without residual neurological deficit. These observations included rolandic sharp waves (comb-like rhythm) which were observed in 7 of 15 patients less than two months of age. Additionally, paroxysmal spike and spike-wave response to photic stimuli were observed in 9 of 17 patients. Loading tests were performed on three patients. Clinical and EEG changes were most marked after leucine. Less dramatic EEG changes also occurred with the other two BCAA loads but without clinical manifestations. Elevation of the appropriate BCAA plasma level occurred after each load. These studies and a review of the literature suggest that one component of the pathophysiological mechanism for the acute neurotoxic effects in this disorder is related to a defect in glutamate, glutamine and gamma-aminobutyric acid (GABA) production. The BCAAs are transaminated to BCKAs. Further metabolism of the BCKAs are blocked because of enzyme deficiency required for decarboxylation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Maple syrup urine disease: clinical, EEG, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity. 774 49

We examined the pharmacological profiles of generalized absence seizures in three mouse models: two mutant strains with spontaneous absence seizures, lethargic and stargazer, and ddY mice (GHB model) in which absence seizures were induced by administering gamma-butyrolactone (GBL), a prodrug of gamma-hydroxybutyric acid (GHB). A typical antiabsence drug, ethosuximide (200 mg/kg), attenuated absence seizure behavior, spike and wave and paroxysmal discharges (SWDs and PDs) in each model. P-[3-Aminopropyl]-P-diethoxymethylphosphinic acid (CGP 35348), a selective gamma-aminobutyric acid (GABA)B antagonist (200 mg/kg), suppressed absence seizure behavior, SWDs and PDs at least as effectively as ethosuximide (200 mg/kg) in lethargic and GHB model mice. P-[3-Aminopropyl]-P-cyclohexylmethylphosphinic acid (CGP 46381) was more effective than CGP 35348 and ethosuximide in these models. Although the antiabsence effect of CGP 46381 was as strong as that of ethosuximide (200 mg/kg) in stargazer mice, CGP 35348 (200-400 mg/kg) was weaker than ethosuximide. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine hydrogen maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) antagonist (0.5 mg/kg), had no effects on SWDs and PDs in lethargic or GHB model mice. Although MK-801 (0.5 mg/kg) suppressed SWDs significantly in stargazer mice, irregular electroencephalographic patterns were observed. These results suggest that GABAB receptors play a significant role in the pathogenesis of generalized absence seizures in these models, although the mechanism involved in stargazer mice differ from that in the other two.
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PMID:Pharmacological profiles of generalized absence seizures in lethargic, stargazer and gamma-hydroxybutyrate-treated model mice. 929 89

To understand the cellular and molecular mechanisms that underlie generalized absence seizures sufficiently well to design rational, efficacious new therapies for patients, it is necessary to turn to animal models to gain insights into these mechanisms. The lethargic (lh/lh) mutant mouse expresses spontaneous absence seizures that share behavioral, electrographic, and anticonvulsant profiles with absence seizures in patients. This validates its use to study the mechanisms that underlie absence seizures. This chapter discusses two scientific approaches that involve the use of lh/lh mice. The first part of the chapter discusses neurobiologic approaches used to investigate critical mechanisms that regulate the synchronized burst firing within the thalamocortical network that generates absence seizures. Two of these critical mechanisms have been studied in detail with lh/lh mice. The first critical mechanism involves the required activation of gamma-aminobutyric acid B (GABAB) receptors to generate absence seizures. Because the numbers of GABAB receptors are increased in thalamocortical populations among lh/lh mice compared with littermates without epilepsy, these receptors appear to play a pathophysiologic role in the expression of absence seizures among lh/lh mice. Moreover, there may be a role for GABAB receptors in the generation of absence seizures among humans, because administration of compounds that activate GABAB receptors can produce absence seizures among humans. These findings suggest that GABAB receptor antagonists may represent a new class of antiabsence compounds that will be efficacious against absence seizures among patients. A second critical mechanism that regulates generation of absence seizures involves GABAA receptors in the nucleus reticularis thalami (NRT), a nucleus that sends GABA-ergic afferents to thalamic relay nuclei. Activation of GABAA receptors in the NRT appears to suppress the generation of absence seizures among lh/lh mice and in other models. Moreover, clonazepam may exert its antiabsence actions through this mechanism. Together, these findings suggest that compounds that selectively activate GABAA receptor isoforms expressed in NRT may represent a class of antiabsence drugs that could have fewer side effects than compounds currently used to treat patients. The second part of the chapter discusses a molecular genetic approach to delineation of the mechanisms that underlie absence seizures. Absence seizures among lh/lh mice are caused by a single-gene defect on chromosome 2. If positional cloning and gene isolation techniques are successful, it will be possible to identify the lh disease gene. Subsequent studies of the lh gene product should greatly increase not only our understanding of the pathophysiologic basis for absence seizures among lh/lh mice but also our ability to seek similar mutations in homologous genes in human families that express absence seizures. Accordingly, strategies and progress in cloning and identifying the lh disease gene are presented.
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PMID:Studies of the lethargic (lh/lh) mouse model of absence seizures: regulatory mechanisms and identification of the lh gene. 1051 18