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)

Levetiracetam is a novel antiepileptic agent with a wide spectrum of activity against experimental and clinical seizures. The mechanism of its anticonvulsant action remains to be determined. We have investigated the effects of levetiracetam on several gamma-aminobutyric acid (GABA)-related neurochemical parameters in mouse brain. Adult male mice were randomised into two groups and administered levetiracetam (0-300 mg/kg) intraperitoneally either as a single dose or twice daily for 5 days. Four hours after the final dose, animals were killed and their brains removed. Brain tissues were analysed for concentrations of GABA, glutamate and glutamine and for the activities of GABA-transaminase and glutamic acid decarboxylase. Single dose and repeated levetiracetam treatments were without effect on all of the parameters investigated. The anticonvulsant action of levetiracetam is unlikely to be mediated via an action on the GABAergic system.
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PMID:Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. 915 36

This study examined brain regional neurotransmitter level changes as a function of seizure duration following soman intoxication. Rats, implanted with cortical electrodes and pretreated with HI-6, received a convulsant dose of soman. At selected times after seizure onset the EEG recording electrodes were removed and the animal was killed. Spinal cord cholinesterase (ChE) activity was rapidly and maximally depressed, while brain acetylcholine (ACh) levels showed elevations as early as 3 min after soman treatment and reached significantly high levels at time of seizure onset. Norepinephrine (NE) levels decreased starting 5 min after seizure onset and continued to decline. Levels of dopamine (DA) and of its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were elevated as early as 5 min after seizure onset and thereafter. The brain levels of aspartate were markedly decreased at and after 20 min of seizures; levels of glutamate were depressed at 80 min in the cortex. Levels of gamma-aminobutyric acid (GABA) were significantly increased in the cortex starting at 20 min after seizure onset, and in the striatum and hippocampus at 80 min after onset. The levels of glutamine, glycine and taurine were not changed at any time studied. These findings are consistent with the notion that inhibition of ChE and elevation of ACh initiate the seizure process, resulting in secondary changes in DA turnover and release of NE, and later changes in excitatory (aspartate, glutamate) and inhibitory (GABA) amino acid transmitters.
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PMID:Neurochemical mechanisms in soman-induced seizures. 928 39

To prevent the hepatotoxicity of valproic acid (VPA), a fluorine substituent was introduced at the alpha-position to eliminate the formation of putative toxic metabolites through mitochondrial beta-oxidation. Although the alpha-fluorinated VPA analogue (alpha-fluoro VPA) is more acidic (pK(a) = 3.55) than VPA (pK(a) = 4.80), the lipophilicity of these two compounds, as determined by their log P values, were similar when compared at pH 2.5. Brain, serum and urine samples were prepared from mature male CD-1 mice treated with either alpha-fluoro VPA or VPA for quantitation of drug concentrations. Brain synaptosomes were isolated to determine gamma-aminobutyric acid levels. After equivalent doses of 0.83 mmol/kg, alpha-fluoro VPA was characterized by its slower access into mouse brain, compared to VPA. The peak concentration of alpha-fluoro VPA in mouse brain was achieved 45 min later than in the serum, whereas the peak brain level of VPA coincided with the peak serum level occurring within 15 min. Simultaneous curve fitting of both brain and serum drug concentrations using a two-compartment model indicated that alpha-fluoro VPA, like VPA, may be asymmetrically transported across the blood-brain-barrier. This property of alpha-fluoro VPA was also reflected in its low brain-to-serum concentration ratio of 0.09 at the peak brain drug concentration (0.16 for VPA). The primary beta-oxidation metabolite of VPA was not found in the serum and urine of mice treated with alpha-fluoro VPA. Although the glucuronide was a major metabolite of VPA (28.5% of the dose), alpha-fluoro VPA was observed to conjugate extensively with L-glutamine (33.3% of the dose). Alpha-fluoro VPA appeared to persist in the general circulation, which, in turn, may contribute to the apparent slow elimination of the drug from the brain. The fluorinated compound was demonstrated to have anticonvulsant activity in the 1,5-pentamethylenetetrazole seizure test and to be capable of increasing brain synaptic gamma-aminobutyric acid, the ED50 being 1.70 mmol/kg. These results suggest that alpha-fluoro VPA has potential as a new anticonvulsant drug.
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PMID:Time course of alpha-fluorinated valproic acid in mouse brain and serum and its effect on synaptosomal gamma-aminobutyric acid levels in comparison to valproic acid. 931 22

Numerous studies suggest that modifications in concentrations of both excitatory and inhibitory amino acids are implicated in the pathophysiology of portal-systemic encephalopathy (PSE), a neuropsychiatric disorder associated with chronic liver disease in humans. In this study, amino acid levels were measured by High Performance Liquid Chromatography (HPLC) in Cerebrospinal Fluid (CSF) of 10 dogs (age range: 3 mo.- 3 yr 4 mo.) exhibiting a congenital portal-systemic shunt, either intra or extra-hepatic, and 8 age-matched control dogs who showed no signs of hepatic or neurologic disorders. Dogs with congenital shunts manifested signs of encephalopathy such as disorientation, head pressing, vocalization, depression, seizures and coma. CSF from dogs with congenital shunts contained significantly increased amounts of glutamate (2 to 3-fold increase, p<0.01), glutamine (6-fold increase, p<0.05) and aromatic amino acids (phenylalanine, tyrosine and tryptophan) compared to CSF of control dogs. Concentrations of GABA and branched chain amino acids (valine, leucine, isoleucine) were within normal limits. Modifications of brain glutamate (an excitatory amino acid) as well as tryptophan (the precursor of serotonin) could contribute to the neurological syndrome characteristic of congenital PSE in dogs.
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PMID:Selective alterations of cerebrospinal fluid amino acids in dogs with congenital portosystemic shunts. 947 3

Cerebral metabolites of a patient with linear nevus sebaceus syndrome and hemimegalencephaly were determined at 18 and 30 months of age by localized proton magnetic resonance spectroscopy. Clinically, the patient suffered from hemiparesis and epileptic seizures. At 18 months of age, spectroscopy of the enlarged hemisphere revealed decreased N-acetylaspartate mainly in parietal white matter relative to the unaffected hemisphere. One year later, white matter studies indicated both reduced N-acetylaspartate and elevated myoinositol. In insular gray matter the previously normal concentrations of creatine, choline-containing compounds, myoinositol, and glutamine were increased. The findings are consistent with mild neuroaxonal loss or damage (white matter) and glial proliferation (cortical gray and white matter) of the affected hemisphere. The metabolic disturbances indicate disease progression but are less pronounced than in older patients with hemimegalencephaly.
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PMID:Proton magnetic resonance spectroscopy of linear nevus sebaceus syndrome. 953 7

The advantages of performing spectroscopic studies at higher field strengths include increased SNR, improved spectral resolution for J-coupled resonances, and improvements in the selectivity of spectral editing schemes. By using pulse sequences that minimize the required echo time, refocus J-evolution, employ low peak B1 requiring pulses and take advantage of spectroscopic imaging methods, these advantages can also be utilized in clinical applications of spectroscopy at high field. In addition to the static measurements measurements of N-acetyl aspartate (NAA), creatine (CR) and choline (CH) which can be performed at 1.5 T, high resolution measurements of glutamate, glutamine, GABA and the incorporation of 13C labeled glucose into glutamate are possible with improved spatial and spectral resolution. These methods have been utilized in patients with seizure disorders and multiple sclerosis to identify, characterize and map the metabolic changes associated with these diseases and their treatment.
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PMID:Biological and clinical MRS at ultra-high field. 954 34

The Pi peak in a 31P NMR spectrum of the brain can be deconvoluted into six separate Lorentzian peaks with the same linewidth as that of the phosphocreatine peak in the spectrum. In an earlier communication we showed that the six Pi peaks in normal brain represent two extracellular and four intracellular compartments. In that report we have identified the first of the extracellular peaks by marking plasma with infused Pi, thereby substantially increasing the amplitude of the single peak at pH 7.35. 2-Deoxyglucose-6-phosphate (2-DG-6-P) was placed in the brain interstitial space by microdialysis. The resulting 2-DG-6-P peak was deconvoluted into three separate peaks. The chemical shift of the principle 2-DG-6-P peak gave a calculated pH of 7.24 +/- 0.02 for interstitial fluid pH, a value that agreed well with the pH of the second extracellular Pi peak at pH 7.25 +/- 0.01. We identified the intracellular compartments by selectively stressing cellular energy metabolism in three of the four intracellular spaces. A seizure-producing chemical, flurothyl, was used to activate the neuron, thereby causing a demand for energy that could not be completely met by oxidative phosphorylation alone. The resulting loss of high-energy phosphate reserves caused a significant increase in intracellular Pi only in those cells associated with the Pi peak at pH 6.95 +/- 0.01. This suggests that this compartment represents the neuron. Ammonia is detoxified in the astrocyte (glutamine synthetase) by incorporating it into glutamine, a process that requires large amounts of glucose and ATP. The intraarterial infusion of ammonium acetate into the brain stressed astrocyte energy metabolism resulting in an increase in the Pi of the cells at pH of 7.05 +/- 0.01 and 7.15 +/- 0.02. This finding, coupled with our observation that these same cells take up infused Pi probably via the astrocyte end-foot processes, lead us to conclude that these two compartments represent two different types of astrocytes, probably protoplasmic and fibrous, respectively. As a result of this study, we now believe the brain contains four extracellular and four intracellular compartments.
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PMID:NMR-based identification of intra- and extracellular compartments of the brain Pi peak. 983 54

Branched-chain amino acids, and mainly leucine act as nitrogen donors in the cerebral glutamate-glutamine cycle, thereby reducing brain excitability. Rats equipped with cortical electrodes received 300 mg/kg of leucine, isoleucine, valine or the ketoacid of leucine, alpha-ketoisocaproate at 2 h before the induction of seizures by 40 mg/kg pentylenetetrazol. Control groups received saline or a commercial mixture of amino acids, Vamine(R). Leucine and isoleucine increased the latency to absence-like and tonic-clonic seizures but did not influence the duration of the tonic-clonic seizure. Vamine(R), valine and alpha-ketoisocaproate had no effect. These data are consistent with the role of leucine in buffering brain glutamate concentration.
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PMID:Modulation of pentylenetetrazol-induced seizure activity by branched-chain amino acids and alpha-ketoisocaproate. 987 52

The study provides a review of the basic examination procedures and results of proton magnetic resonance spectroscopy (1H MRS) in patients suffering from mesial temporal lobe epilepsy (MTLE). The source of seizures in MTLE is most often an epileptogenic focus secondary to hippocampal sclerosis. 1H MRS currently plays an important role in the non-invasive diagnosis of this type of epileptogenic lesion. The decisive 1H MRS parameter characterizing an epileptogenic lesion is a statistically significantly decreased value of N-acetylaspartate levels compared with control values, most often associated with a decrease in the ratios of the intensities of NAA/Cr, NAA/Cho and NAA/(Cr + Cho) signals. Moreover, MRS makes it possible to distinguish bilateral involvement of mesial temporal structures typically associated with a bilateral decrease in the levels of metabolites and/or their ratios. As regards other metabolic compounds which play an important role in the pathobiochemistry of epilepsy, MRS is employed to study the action of gamma-aminobutyric acid (GABA), inositol, lactate, glutamine, and glutamate, the clinical function of which has not been fully clarified as yet. It is in this context that one should consider the application of 1H MRS in evaluating the action of some new anti-epileptic agents affecting excitatory and inhibitory amino acids. There is no doubt that in vivo 1H MRS, along with other imaging methods, has made a significant contribution to the clinical and biochemical description of epileptic seizures and has assumed a prominent position among the techniques of pre-operative examination in epileptic surgery.
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PMID:1H MR spectroscopy in patients with mesial temporal epilepsy. 995 70

Kainate (KA) is a potent neuroexcitatory agent in several areas of the adult brain, with convulsant and excitotoxic properties that increase as ontogeny proceeds. Besides its depolarizing actions, KA may enhance intracellular accumulation of Ca2+ to promote selective neuronal damage. The effects of KA are mediated by specific receptors recently considered to be involved in fast neurotransmission and that can be activated synaptically. KA receptors, e.g. GluR5 and GluR6 have been characterized by molecular cloning. Structure-function relationships indicate that in the MII domain of these KA receptors, a glutamine (Q) or arginine (R) residue determines ion selectivity. The arginine stems from post-transcriptional editing of the GluR5 and GluR6 pre-RNAs, and the unedited and edited versions of GluR6 elicit distinct Ca2+ permeability. Using a PCR-based approach, we show that in vivo, Q/R editing in the GluR5 and GluR6 mRNAs is modulated during ontogeny and differs substantially in a variety of nervous tissues. GluR5 editing is highest in peripheral nervous tissue, e.g. the dorsal root ganglia, where GluR6 expression is barely detectable. In contrast, GluR6 editing is maximal in forebrain and cerebellar structures where GluR5 editing is lower. Intra-amygdaloid injections of KA provide a model of temporal lobe epilepsy, and we show that following seizures, the extent of GluR5 and GluR6 editing is altered in the hippocampus. However, in vitro, high levels of glutamate and potassium-induced depolarizations have no effect on GluR5 and GluR6 Q/R editing. GluR6 editing is rapidly enhanced to maximal levels in primary cultures of cerebellar granule neurons but not in cultured hippocampal pyramidal neurons. Finally, we show that cultured glial cells express partially edited GluR6 mRNAs. Our results indicate that Q/R editing of GluR5 and GluR6 mRNAs is structure-, cell type- and time-dependent, and suggest that editing of these mRNAs is not co-regulated.
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PMID:Q/R editing of the rat GluR5 and GluR6 kainate receptors in vivo and in vitro: evidence for independent developmental, pathological and cellular regulation. 1005 61


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