Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Rett syndrome (RS) is a peculiar, sporadic, atrophic disorder, almost entirely confined to females. After the first six months of life there is developmental slowing with reduced communication and head growth for about one year. This is followed by a rapid destructive stage with severe dementia and loss of hand skills (with frequent hand wringing), apraxia and ataxia, autistic features and irregular breathing with hyperventilation. Seizures often supervene. Subsequently there is some stabilization in a pseudo-stationary stage during the preschool to school years, associated with more emotional contact but also abnormalities of the autonomic and skeletal systems. After the age of 15-20 years, a late motor deterioration occurs with dystonia and frequent spasticity but seizures become milder. RS has generally been considered an X-linked disorder in which affected females represent a new mutation, with male lethality. Linkage studies suggested a critical region at Xq28. In 1999, mutations in the gene MECP2 encoding X-linked methyl cytosine-binding protein 2 (MeCP2) were found in a proportion of Rett girls. This protein can bind methylated DNA. Analyses are leading to much further investigation of mutants and their effects on genes. Neuropathological and electrophysiological studies of RS are described. Description of neurometabolic factors includes reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. The results of neuroimaging are surveyed, including volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET).
 ...
PMID:Rett syndrome: review of biological abnormalities. 1125 89

The syndrome of brain atrophy in girls described by Andreas Rett in 1966 [Rett, Wien Klin Wochenschr, 1966;116:723-726] was brought to the attention of the English-speaking world by Hagberg et al. in 1983 [Hagberg et al., Ann Neurol, 1983;14:471-479]. Four clinical stages after the age of 6 months were described in classical cases of Rett syndrome (RS), namely early onset stagnation at 6 months to 1(1/2) years, the rapid destructive stage at 1-3 years, the pseudo-stationary stage from pre-school to school years, and the late motor deterioration stage at 15-30 or more years. The rapid destructive stage causes profound dementia with loss of speech and hand skills, stereotypic movements, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequently seizures. Most cases are isolated in their families, apart from identical twins. However, linkage studies in rare familial cases suggested a critical region at Xq28. In 1999 American investigators found several mutations in the X-linked gene MECP2 encoding Methyl-CpG-binding protein 2 in a proportion of Rett patients. The protein MeCP2 can bind methylated DNA and when mutated may interfere with transcriptional silencing of other genes and result in abnormal chromatin assembly. Many different mutations of the protein are being studied in humans and in mice. Neuropathological studies have shown decreased brain growth and decreased size of individual neurons, with thinned dendrites in some cortical layers, and abnormalities in substantia nigra, suggestive of deficient synaptogenic development, probably starting before birth. Electrophysiology demonstrates progressively abnormal electroencephalograms (EEG) in the first three stages of the syndrome, with some subsequent improvement and occurrence of pseudoseizures. Neurometabolic factors are discussed in detail, particularly reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. Autonomic dysfunction is described, particularly reduced vagal and overactive sympathetic activity. Neuro-imaging may be required for further investigation, as shown in the differential diagnosis.
 ...
PMID:Importance of Rett syndrome in child neurology. 1173 40

Galanin overexpressing transgenic mice (GAL-tg) were generated on two different promoters. Both lines of GAL-tg displayed high levels of galanin in the hippocampus and reduced sensitivity to seizures, as compared to their respective wildtype littermate controls (WT). Performance deficits on learning and memory tasks, impaired long-term potentiation, reduced hippocampal excitability, lower evoked glutamate release, and reduced numbers of choline acetyltransferase immunoreactive neurons in the horizontal limb of the diagonal band were detected in GAL-tg as compared to WT. Changes in sensitivity to nociceptive stimuli were demonstrated in one line. GAL-tg represent a new model for investigating the biological actions of endogenous galanin, and for testing novel therapeutics based on galanin receptor ligands.
 ...
PMID:Galanin overexpressing transgenic mice. 1235 5

The effects of sodium azide administration on the central cholinergic functions were investigated utilizing mice to evaluate the neurotoxicity in the acute poisoning. Seven oral doses of the toxicant, ranging in dosage from 12.3 to 59.3 mg/kg, based upon a multiple of 1.3 x 27 mg/kg (an empirical LD50 for mice) or 27 mg/kg divided by 1.3 to calculate the lower three doses, were administered to facilitate the acute signs and to observe behavior. The behavior included locomotor activity, rectal temperature and rotarod performance which are convenient for the evaluation of central cholinergic involvement even if it may be partial, since no behavioral methods to study totally the cholinergic system have been known. Measurements of the activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), enzymes that hydrolyze and synthesize acetylcholine (ACh) and high-affinity choline uptake (HACU), a rate-limiting step in the synthesis of ACh, were determined in the presence of various concentrations of sodium azide in vitro. Adult (12-15 weeks) female ICR strain mice were utilized in this study. Mice were orally given sodium azide in doses from 27 to 59.3 mg/kg and appeared sedated within 5 min. Next we observed hyperpnea and dyspnea, which were followed by seizure and death for mouse groups which received more than 35.1 mg/kg. Oral administration of the sodium azide solution produced an increase in locomotor activity for the 12.3 mg/kg group and a decrease for the higher doses (ranging from 16.0 to 27.0 mg/kg). The sodium azide administration suppressed rectal temperature dose-dependently as well as rotarod performance at high doses (20.8 and 27.0 mg/kg). Such behavioral changes elicited by sodium azide administration suggest an involvement of the central cholinergic system. Sodium azide also caused a measured decrease in the activity of AChE, but an increase in the activities of ChAT and HACU, dose-dependently, in vitro. From the results obtained from the behavioral and the in vitro experiments, we concluded that acute sodium azide poisoning significantly affects the central cholinergic system.
 ...
PMID:[Neurotoxicity in sodium azide poisoning]. 1241 70

Rett syndrome is a progressive, usually sporadic and rarely familial, disabling neurodevelopmental disorder with onset in early childhood presenting clinically with mental retardation, behavioral changes, late movement disturbances, loss of speech and hand skills, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequent seizures. It occurs almost exclusively in females with an estimated prevalence of 1 in 10-22000 births and is considered a manifestation of defective brain maturation caused by dominant mutation of the MeCP2 gene encoding the transcriptional repressor methyl-CpG-binding protein 2 related to the Xq28 locus. Although many different mutations of this protein are being studied in humans and in mice, the molecular pathogenesis of this disorder remains unclear. Electroencephalography is abnormal in the final stages of the syndrome. Neuroimaging showing brain atrophy may be required for differential diagnosis that includes neurodegenerative and metabolic disorders. Neuropathology shows decreased brain growth and reduced size of individual neurons, with thinned dendrites in some cortical layers and abnormalities in substantia nigra (decreased neuromelanin content), suggestive of deficient synaptogenic development, probably starting before birth. Neurometabolic changes include reduced levels of dopamine, serotonin, noradrenalin, choline acetyltransferase (ChAT), nerve growth factors, endorphines, glutamate, and other amino acids and their receptor levels in brain. Current treatment includes symptomatic, anticonvulsive and physiotherapy.
 ...
PMID:Rett Syndrome -- an update. 1276 63

Paediatric hemimegalencephaly (HME) is a congenital central nervous system (CNS) disorder, characterized by monolateral cerebral hemisphere enlargement, intractable seizures starting in the post-neonatal period, and mental retardation associated with neuropathological anomalies (mainly cortical thickness and lack of lamination). Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two neurotrophic factors produced in the mammalian CNS that are involved in the survival, development, and function of a variety of brain cells. In the present study, we found increased cerebral tissue levels of NGF and BDNF in 4 infants with HME; these changes appear to be also associated with abnormal NGF-receptor expression in subcortical blood vessels. Moreover, the marked reduction of cortical choline acetyltransferase immunoreactivity is strongly suggestive of a dysregulation in the NGF differentiative activity in this site that could lead to the pathogenesis of HME.
 ...
PMID:Nerve growth factor and brain-derived neurotrophic factor in human paediatric hemimegalencephaly. 1500 51

The aim of the study was to investigate neurochemical changes in a kainic acid (KA; 10 mg/kg, s.c.)-induced spontaneous recurrent seizure model of epilepsy, 6 months after the initial KA-induced seizures. The neuronal markers of cholinergic and gamma-aminobutyric acid (GABA)ergic systems, i.e. choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activities, and a marker for neuropeptide, i.e. level of somatostatin, have been investigated. The brain regions investigated were the hippocampus, amygdala/piriform cortex, caudate nucleus, substantia nigra and the frontal, parietal, temporal and occipital cortices. Six months after KA injection, reduced ChAT activity was observed in the amygdala/piriform cortex (47% of control; p<0.001), increased ChAT activity in the hippocampus (119% of control; p<0.01) and normal ChAT activity in the other brain regions. The activity of GAD was significantly increased in all analysed cortical regions (between 146 and 171% of control), in the caudate nucleus (144% of control; p<0.01) and in the substantia nigra (126% of control; p<0.01), whereas in the amygdala/piriform cortex, the GAD activity was moderately lowered. The somatostatin level was significantly increased in all cortical regions (between 162 and 221% of control) as well as in the hippocampus (119% of control), but reduced in the amygdala/piriform cortex (45% of control; p<0.01). Six months after KA injection, the somatostatin:GAD ratio was lowered in the amygdala/piriform cortex (49% of control) and in the caudate nucleus (41% of control), whereas it was normal in the hippocampus and moderately increased in the cortical brain regions. A positive correlation was found between seizure severity and the reduction of both ChAT activities and somatostatin levels in the amygdala/piriform cortex. The results show a specific pattern of changes for cholinergic, GABAergic and somatostatinergic activities in the chronic KA model for epilepsy. The revealed data suggest a functional role for them in the new network that follows spontaneous repetitive seizures.
 ...
PMID:Choline acetyltransferase, glutamic acid decarboxylase and somatostatin in the kainic acid model for chronic temporal lobe epilepsy. 1562 16

Tottering (tg/tg) and leaner (tg(la)/tg(la)) mutant mice exhibit distinct mutations in the gene encoding the voltage-activated Ca(2+) channel alpha(1A) subunit (CACNA1A), the pore-forming subunit of the Ca(V)2.1 (P/Q type) Ca(2+) channels. These mice exhibit absence seizures and deficiencies in motor control and other functions. Previous work in cerebellar Purkinje neurons has shown that these mutations cause dramatic reductions in calcium channel function. Because Purkinje cell somata primarily express the Ca(V)2.1 channels, the general decrease in Ca(V)2.1 channel function is observed as a profound decrease in whole-cell current. In contrast to Purkinje cells, basal forebrain (BF) neurons express all of the Ca(2+) channel alpha(1) subunits, with Ca(V)2.1 contributing approximately 30% to the whole-cell current in wild-type (+/+) mice. Here, we show that whole-cell Ba(2+) current densities in BF neurons are not reduced in the mutant genotypes despite a reduction in the Ca(V)2.1 contribution. By blocking the different Ca(2+) channel subtypes with specific pharmacological agents, we found a significant increase in the proportion of Ca(V)1 Ca(2+) current in mutant phenotypes. There was no change in tissue mRNA expression of calcium channel subtypes Ca(V)2.1, Ca(V)2.2, Ca(V)1.2, Ca(V)1.3, and Ca(V)2.3 in the tottering and leaner mutant mice. These results suggest that Ca(V)1 channels may functionally upregulate to compensate for reduced Ca(V)2.1 function in the mutants without an increase in Ca(v)1 message. Single-cell reverse transcription polymerase chain reaction (RT-PCR) experiments in a subset of sampled neurons revealed that approximately 90% of the cells could be considered cholinergic based on choline acetyltransferase (ChAT) mRNA expression.
 ...
PMID:Functional compensation by other voltage-gated Ca2+ channels in mouse basal forebrain neurons with Ca(V)2.1 mutations. 1636 58

The septal region of the basal forebrain plays a critical role modulating hippocampal excitability and functional states. Septal circuits may also play a role in controlling abnormal hippocampal hyperexcitability in epilepsy. Both lateral and medial septal neurons are targets of hippocampal axons. Since the hippocampus is an important epileptogenic area in temporal lobe epilepsy, we hypothesize that excessive excitatory output will promote sustained neurodegeneration of septal region neurons. Pilocarpine-induced status epilepticus (SE) was chosen as a model to generate chronic epileptic animals. To determine whether septal neuronal populations are affected by hippocampal seizures, immunohistochemical assays were performed in brain sections obtained from age-matched control, latent period (7 days post-SE) and chronically epileptic (more than one month post-SE survival) rats. An anti-NeuN (neuronal nuclei) antibody was used to study total neuronal numbers. Anti-ChAT (choline acetyltransferase), anti-GAD (glutamic acid decarboxylase) isoenzymes (65 and 67), and anti-glutamate antibodies were used to reveal cholinergic, GABAergic and glutamatergic neurons, respectively. Our results revealed a significant atrophy of medial and lateral septal areas in all chronically epileptic rats. Overall neuronal density in the septum (medial and lateral septum), assessed by NeuN immunoreactivity, was significantly reduced by approximately 40% in chronically epileptic rats. The lessening of neuronal numbers in both regions was mainly due to the loss of GABAergic neurons (80-97% reduction in medial and lateral septum). In contrast, populations of cholinergic and glutamatergic neurons were spared. Overall, these data indicate that septal GABAergic neurons are selectively vulnerable to hippocampal hyperexcitability, and suggest that the processing of information in septohippocampal networks may be altered in chronic epilepsy.
 ...
PMID:Septal GABAergic neurons are selectively vulnerable to pilocarpine-induced status epilepticus and chronic spontaneous seizures. 1693 46

In the present study we investigated the effect of seizures on rat performance in the Morris water maze task, as well as on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in rat hippocampus. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (20 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (20 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of LA (LA plus pilocarpine group). After the treatments all groups were observed for 1 h. The effect of lipoic acid administration was observed on reference and working spatial memory of seized rats. The ChAT and AChE activities were measured using spectrophotometric methods and the results compared to values obtained from saline and pilocarpine-treated animals. Its activity was also determined after behavioral task. Results showed that pretreatment with lipoic acid did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant day's effect with significant differences between control and pilocarpine-induced seizures and pretreated animals with lipoic acid. In LA plus pilocarpine group was observed a significantly increased in ChAT and AChE activities, when compared to pilocarpine group. Results showed that acute administration of lipoic acid alone did not alter hippocampal ChAT and AChE activities. Our findings suggest that seizures caused cognitive dysfunction and a decrease of ChAT and AChE activities that might be related, at least in part, to the neurological problems presented by epileptic patients. Lipoic acid can reverse cognitive dysfunction observed in seized rats as well as increase the ChAT and AChE activities in hippocampus of rats prior to pilocarpine-induced seizures, suggesting that this antioxidant could be used in clinic treatment of epilepsy.
 ...
PMID:Lipoic Acid increases hippocampal choline acetyltransferase and acetylcholinesterase activities and improvement memory in epileptic rats. 1966 75


<< Previous 1 2 3 4 5 Next >>