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)

Previous results have shown that kindled seizures increase N-acetyl-aspartylglutamate (NAAG) levels in the entorhinal cortex, while non-kindled convulsions have no effect. To further explore possible relationships between epilepsy and the physiology of NAAG, the effect of amygdaloid kindling on the activity of a NAAG-hydrolyzing enzyme was examined in specific brain regions associated with limbic seizures. NAAG is hydrolyzed into glutamate (Glu) and N-acetyl-aspartate (NAA) by N-acetylated-alpha-linked acidic dipeptidase (NAALADase), a membrane-bound peptidase. We found that convulsions decreased NAALADase activity and these effects were generalized to several brain regions. While small decreases in the hippocampus were specific to kindling, the decreases in other limbic regions were larger, non-specific, and appear to be aftereffects of convulsions; i.e. not specific to kindling. Although there is evidence that NAAG may be an excitatory neurotransmitter, it could also function as a storage form of Glu. Thus, a reduction in NAALADase activity could reduce the availability of Glu at certain synapses, which might be a homeostatic mechanism for lessening susceptibility to further seizures.
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PMID:Seizures decrease regional enzymatic hydrolysis of N-acetyl-aspartylglutamate in rat brain. 261 66

The anticonvulsant effect of compounds that inhibit peptidyl-dipeptidase (PDP) on bicuculline (BIC)- and strychnine (STRYC)-induced seizures was assessed after intracerebroventricular (ICV) or intraperitoneal (IP) administration in Swiss albino mice. STRYC-induced seizures were delayed by ICV injections and high IP doses of captopril, but not by ICV or IP injections of enalapril or by lower doses of captopril (0.1 mg/kg and 1 mg/kg IP). BIC-induced seizures were not suppressed by ICV or IP injections of either compound; on the contrary, captopril and enalapril exhibited proconvulsant effects when given IP or ICV by shortening the time of onset of tonic seizures and death. Results indicate that the anticonvulsant effect of captopril against STRYC-induced seizures is not mediated by central gamma-aminobutyric acid (GABA) receptors or by the inhibition of PDP.
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PMID:Effect of peptidyl-dipeptidase inhibitors in experimental convulsions in mice. 282 10

A case of false-negative Tc-99m MDP bone scintigrams, taken at one and two weeks for pathologic fractures in a patient with metabolic bone disease and a super-scan appearance, is described. The patient had renal osteodystrophy, and postparathyroidectomy hypocalcemia. Postoperative seizures caused multiple pathologic fractures. Initial scans were negative for focal tracer localization in the presence of a continued super-scan appearance. After months of calcium and vitamin D replacement therapy, fracture sites became positive on Tc-99m MDP imaging. The observations in this case lend credence to the hypothesis of Tc-99m MDP binding by immature collagen in the production of a super scan in metabolic bone disease, as well as that of Tc-99m MDP chemisorption to calcium hydroxyapatite crystal in fracture healing. In addition, aluminum toxicity, common in chronic renal osteodystrophy, may have played a role in the delayed fracture healing.
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PMID:Pathologic fractures in a patient with renal osteodystrophy. Failure of early detection on bone scans. 360 30

Primarily on the basis of activity in [3H]phencyclidine (PCP) binding assays and drug discrimination studies, a number of structurally dissimilar compounds have been found to be PCP-like. Drugs from four of these classes of PCP-like compounds were examined for anticonvulsant activity in the pentylenetetrazol (PTZ) seizure test. Male albino mice, eight per dose, were administered the drug or vehicle i.p. 10 min before PTZ (125 mg/kg s.c.). At each dose, the number of subjects and latency to clonic and/or tonic seizures within 15 min following PTZ were recorded. The anticonvulsant properties of PCP, ketamine, (+)-N-allylnormetazocine, etoxadrol, dexoxadrol and (-)-2-methyl-3,3-diphenyl-3-propanolamine ((-)-2-MDP) were selective for tonic seizures. The highest dose tested for each compound completely prevented the occurrence of tonic seizures. Levoxadrol and (+)-2-MDP, drugs devoid of PCP-like activity in other tests, were also inactive in the PTZ seizure test. These results demonstrate that similarities among PCP-like drugs previously shown using binding assays and drug discrimination procedures can be extended to include anticonvulsant effects, and they suggest common cellular sites of action for these properties.
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PMID:Anticonvulsant properties of phencyclidine-like drugs in mice. 408 41

There is mounting evidence, primarily from research in experimental animals, that the dipeptide N-acetylaspartylglutamate (NAAG) and its metabolic enzyme, N-acetylated alpha-linked acid dipeptidase (NAALADase), are involved in glutamatergic neurotransmission. Previous studies in neuropsychiatric disorders associated with the dysregulation of glutamatergic neurotransmission, such as schizophrenia, seizure disorders, and amyotrophic lateral sclerosis (ALS), have revealed region-specific alterations in the levels of NAAG and in the activity of NAALADase. To establish better the cellular localization of these and related parameters in human brain, we have examined their alterations in two well-characterized selective neurodengenerative disorders, Huntington Disease (HD) and Alzheimer Disease (AD). Brain regions from postmortem controls and HD- or AD-affected individuals were assayed to determine the activity of NAALADase as well as the levels of NAAG, N-acetylaspartate (NAA), and several amino acids. The relationships between changes in these neurochemical parameters and changes in neuronal and glial cell density were determined. The present report demonstrates that the decreases in the levels of NAAG and NAA and in the activity of NAALADase in AD and HD brain correlate primarily with neuronal loss. By inference, the results suggest that NAAG and NAA have primarily a neuronal localization in human brain and that there is a close relationship between NAAG and the dipeptidase NAALADase in populations of affected neurons.
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PMID:N-acetylaspartylglutamate, N-acetylaspartate, and N-acetylated alpha-linked acidic dipeptidase in human brain and their alterations in Huntington and Alzheimer's diseases. 937 25

We have evaluated the effects of the N-acetylated-alpha-linked acidic dipeptidase (NAALADase) inhibitor, GPI5232 [2-[(pentafluorophenylmethyl)hydroxyphosphinyl]methyl)-pentanedioic acid], to not only decrease brain injury but also to alter the inherent electroencephalographic (EEG) changes observed in a rat model of transient middle cerebral artery occlusion (MCAo). Continuous i.v. infusion of GPI5232 starting 1 h after injury resulted in more than a 50% reduction in brain infarct volume caused by 2 h of MCAo. This effect was dose-dependent and significant even when first treatment was delayed for 2 h post-MCAo. At 24 h post-MCAo, EEG spectral analysis of the injured hemisphere revealed functional improvement in GPI5232-treated rats. Significant recovery in high-frequency EEG power (8-30 Hz) was measured in GPI5232-treated animals in both parietal and temporal brain regions but not in vehicle-treated animals. MCAo-injured rats were also predisposed to developing cortical brain seizures, and GPI5232-treated rats had significantly fewer brain seizures than vehicle-treated animals. In separate experiments, acute high doses of GPI5232 in normal rats did not significantly alter EEG brain activity as evaluated by spectral analysis and did not produce any signs of seizure activity or behavioral abnormalities. These results show GPI5232 to be an effective neuroprotective treatment when given postinjury by reducing brain infarction and ameliorating the pathological EEG associated with focal brain ischemia.
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PMID:Electroencephalogram analysis and neuroprotective profile of the N-acetylated-alpha-linked acidic dipeptidase inhibitor, GPI5232, in normal and brain-injured rats. 1156 Oct 62

We investigated the effect of intense audiogenic stimulation (AGS) on rats treated with the antibiotic imipenem and dipeptidase inhibitor cilastatin (Imi/Cil). Under pentobarbital anesthesia (40 mg/kg) adult male Wistar rats were implanted with electrodes and cannulas were placed in the right lateral ventricle. Animals were divided into the following groups: (1) vehicle, (2) Imi/Cil 10 microg/10 microg, (3) Imi/Cil 25 microg/25 microg, (4) vehicle+AGS, (5) Imi/Cil 10 microg/10 microg +AGS, and (6) Imi/Cil 25 microg/25 microg +AGS. Imi/Cil was administered intracerebroventricularly in 5 microl of physiological saline. AGS (100+/-3 dB, 60 seconds) was applied at 15-minute intervals after the injection. Imi/Cil-induced seizures (twitching, forelimb clonus, headnodding, rearing, and clonic convulsions) and Imi/Cil-audio-induced seizures (wild running, clonic and tonic convulsions) were scored according to appropriate rating scales. Imi/Cil provoked convulsions dose-dependently. Each behavioral seizure response had a characteristic EEG correlate. AGS by itself did not provoke seizures in untreated rats. Sound stimulation in Imi/Cil-injected rats elicited typical audiogenic seizures, which were induced during five AGS tests (75 minutes postinjection). In most cases audiogenic seizures were not associated with epileptiform activity in the EEG, indicating that spreading of seizures did not involve the cortex. Since Imi/Cil-induced and Imi/Cil-audio-induced seizures differed behaviorally and electroencephalographically, it is suggested that different neural pathways are responsible for these two types of seizures: neuronal networks in the cortex are involved in Imi/Cil-induced seizures, whereas audiogenic seizures use networks residing primarily in the brainstem.
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PMID:Induction of audiogenic seizures in imipenem/cilastatin-treated rats. 1512 14

This paper describes the structural elucidation of a compound produced during the synthesis of 3,4-methylenedioxymethylamphetamine (MDMA) via the reductive amination of 3,4-methylenedioxyphenyl-2-propanone (3,4-MDP-2-P) with methylamine and sodium cyanoborohydride. The compound was isolated from MDMA by column chromatography, proton and carbon nuclear magnetic resonance spectroscopy, LC/mass spectrometry, and total synthesis were used to identify the compound as N-cyanomethyl-N-methyl-1-(3',4'-methylenedioxyphenyl)-2-propylamine. This compound has been identified as a potential synthetic route marker for the reductive amination of 3,4-MDP-2-P with methylamine and sodium cyanoborohydride and as such it should prove valuable to forensic scientists engaged in profiling illicit drugs. Profiling MDMA can provide useful information to law enforcement agencies relating to synthetic route, precursor chemicals and reagents employed and may be used for comparative analyses of different drug seizures. This paper also describes the structural elucidation of the analogous methylamphetamine synthetic route marker compound, N-cyanomethyl-N-methyl-1-phenyl-2-propylamine, produced during the reductive amination of phenyl-2-propanone using methylamine and sodium cyanoborohydride.
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PMID:N-cyanomethyl-N-methyl-1-(3',4'-methylenedioxyphenyl)-2-propylamine: an MDMA manufacturing by-product. 1863 69