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)

The purpose of this research was to characterize by X-ray crystallography the ternary dimethylformamide (DMF) Cu(II) complex of acetylsalicylic acid (aspirin), in an effort to compare the structure-activity relationships for the anticonvulsant activity of this and other Cu(II)aspirinate chelates. The ternary DMF Cu(II) complex of aspirin was synthesized and crystals grown from a DMF solution were characterized by single crystal X-ray diffraction. This crystalline material was analyzed for anticonvulsant activity in the Maximal Electroshock (MES) Grand Mal and subcutaneous Metrazol (scMET) Petit Mal models of seizure used to detect anticonvulsant activity. The ternary DMF complex was found to be a monomolecular binuclear complex, tetrakis-mu-(acetylsalicylato)bis(dimethylformamido)dicopper(II) [Cu(II)(2)(aspirinate)(4)(DMF)(2)] with the following parameters: monoclinic, space group P2(1)/n, a=12.259 (1), b=10.228 (1), c=16.987 (1) A, beta=92.07 (1) degrees; V=2128.5 (3) A(3); Z=2. The structure was determined at 180 K from 2903 unique reflections (I>1sigma(I)) to the final values of R=0.030 and wR=0.033 using F. This binuclear complex contains four acetylsalicylate bridging ligands which are related to each other in a two by two symmetry center. The four nearest O atoms around each Cu atom form a closely square planar arrangement with the square pyramidal coordination completed by the dimethylformamide oxygen atom occupying an apical position at a distance of 2.154 (1) A. Each Cu atom is displaced towards the DMF ligand by 0.187 A from the plane of the four O atoms. Electron paramagnetic resonance (EPR) spectra of [Cu(II)(2)(aspirinate)(4)(DMF)(2)] crystals show a strong antiferromagnetic coupling of the copper atoms, similar to that observed with other binuclear copper(II)salicylate compounds. Studies used to detect anticonvulsant activity revealed that [Cu(II)(2)(aspirinate)(4)(DMF)(2)] was an effective anticonvulsant in the MES model of seizure but ineffective against scMET-induced seizures. The monomolecular ternary binuclear [Cu(II)(2)(aspirinate)(4)(DMF)(2)] complex is more effective in inhibiting MES-induced seizures than other binuclear or mononuclear Cu(II) chelates of aspirin including: binuclear polymeric [Cu(II)(2)(aspirinate)(4)], [Cu(II)(2)(aspirinate)(4)(H(2)O)], which is anticipated to be less polymeric, and monomolecular ternary [Cu(II)(2)(aspirinate)(4)(DMSO)(2)] and [Cu(II)(aspirinate)(2)(Pyr)(2)]. These and other chelates appear to be more effective in the scMET model of seizure than [Cu(II)(2)(aspirinate)(4)(DMF)(2)]. These structure-activity relationships support the potential efficacy of Cu chelates of aspirin in treating epilepsies.
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PMID:Low-temperature (180 K) crystal structure, electron paramagnetic resonance spectroscopy, and propitious anticonvulsant activities of CuII2(aspirinate)4(DMF)2 and other CuII2(aspirinate)4 chelates. 1288 73

Non-Asian individuals with Down syndrome are much more likely to develop epileptic seizure disorders than individuals without Down syndrome. Examination of nutrient and metabolite levels in patients with these two seemingly disparate disorders reveals numerous similarities. Compared to individuals without these disorders, individuals with Down syndrome and individuals with seizures may have lower levels of vitamin A, vitamin B1, folate, vitamin B12, vitamin C, magnesium, manganese, selenium, zinc, carnitine, carnosine, choline, and possibly serine. Excesses of copper, cysteine, phenylalanine, and superoxide dismutase are also sometimes encountered in both disorders. In addition to common nutritional lower levels and excesses, disorders of metabolism involving vitamin B6, vitamin D, calcium, and tryptophan may play a common role. This paper hypothesizes that nutritional factors may account for the high joint occurrence of these conditions. Further examination of these data may provide insights into nutritional, metabolic and pharmacological treatments for both conditions.
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PMID:Down syndrome and epilepsy: a nutritional connection? 1472 2

Creutzfeldt-Jakob disease (CJD) is a presenile dementia characterized by rapidly progressive mental deterioration, myoclonic jerking, and other less common neurological signs. Few autoctonous cases have been described in Brazil. A 54-year-old white woman, was admitted in our service with a month history of progressive, bilateral cortical blindness. After admission, she developed right partial motor seizures( right facial, upper and lower limbs), she became progressively aphasic( mixed aphasia). Seizures were controlled with phenytoin, but she developed choreoathetotic movements on her right dimidium, with partial control after introduction of chlorpromazine 25 mg q/d. She could no longer stand up or walk due to severe ataxia. The first EEG (October, 2001) showed left hemisphere severe seizure activity (status epilepticus partialis). She was delivered home with enteral nutrition, phenytoin, chlorpromazine and mepacrine 100 mg qd. The following laboratorial tests were negative or normal: blood series, platelets, ESR, kidney and liver function, copper, ceruloplasmin, VDRL, HIV, HTLV-1, lactate, and cerebral DSA (performed in other service).A spinal tap with normal opening pressure was perform and CSF examination was normal. CSF 14-3-3 protein was positive, CSF specific neuronal enolase 7.5 ng/ml(normal). Genetic study of PRNP gene did not disclosed any known mutation. A MRI (October, 2001) showed areas of hyperintense signal (T2 and FLAIR) without Gd-enhancement on T1, in the left temporal lobe and in both occipital lobes; basal ganglia have a normal appearance. DWI imaging showed bright areas at the same sites. An EEG (March, 2002) disclosed a periodical sharp triphasic waves pattern, suggestive of CJD. A second MRI (April, 2002) showed mild generalized atrophy, no ventricular dilatation, and the hyperintense sites disappeared. She remained clinically stable and under use of chlorpromazine and mepacrine until she died due to pulmonary complications on April, 2003.
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PMID:[Creutzfeldt-Jakob disease, Heidenhain variant: case report with MRI (DWI) findings]. 1523 44

Epileptic patients exhibited variably altered status of trace elements, electrolytes, and free radical scavenging enzyme activities. We investigated the effect of epilepsy and long-term antiepileptic drug therapy on the serum level of some trace elements (zinc, selenium, and copper), electrolytes (calcium, magnesium, sodium, and potassium), and antioxidants (glutathione peroxidase, and uric acid) and plasma levels of lipid peroxidation index (malondialdehyde), total antioxidant capacity, and ceruloplasmin. Seventy epileptic patients and fourteen controls were recruited in this study. In the treated group (particularly with valproate), we reported increases in the levels of zinc, calcium, sodium, malondialdehyde, and glutathione peroxidase and decreases in the levels of copper, total antioxidant capacity, and ceruloplasmin with no difference in selenium, magnesium, and potassium. However among untreated epileptics, uric acid level was increased and total antioxidant capacity was markedly lowered. We conclude that the above parameters balance differs in epileptics comparable to controls and hence their correlation to seizures pathophysiology and their degree of control or resistance to antiepileptic drug therapy. Better regulation of the lipid peroxidation and antioxidants and fewer disturbances in mineral metabolism were observed in monotherapy versus polytherapy and with carbamazepine versus valproate therapy.
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PMID:Blood levels of trace elements, electrolytes, and oxidative stress/antioxidant systems in epileptic patients. 1559 98

Two pseudopolymorphs, solvates, of [Cu(2)(II)(niflumate)(4)(H(2)O)(2)] of unknown structure were obtained following solution of [Cu(2)(II)(niflumate)(4)(H(2)O)(2)] in N,N-dimethylacetamide (DMA) or N,N-dimethylformamide (DMF). Low-temperature crystal structures obtained for these solvates revealed that they were ternary aqua DMA and DMF solvates: [Cu(2)(II)(niflumate)(4)(H(2)O)(2)].4DMA and [Cu(2)(II)(niflumate)(4)(H(2)O)(2)].4DMF. Intermolecular hydrogen bonding interactions account for the formation of these stable DMA and DMF solvates. These pseudopolymorphs contain a centrosymmetric binuclear center with Cu-Cu bond distances ranging from 2.6439(7) to 2.6452(9) A; the coordination sphere of Cu(II) is characterized by one long Cu-O (water) bond length of 2.128(3)-2.135(3) A and four short Cu-O (carboxylate) bonds of 1.949(3)-1.977(3) A. Crystal parameters for the DMA pseudopolymorph: a=10.372(1), b=19.625(2), c=17.967(2) A, beta=97.40(1) degrees , V=3626.8(6) A(3); monoclinic system; space group: P2(1)/a and for the DMF pseudopolymorph: a=10.125(2), b=18.647(3), c=19.616(4) A, alpha=74.38(2)(o), beta=88.18(2)(o), gamma=79.28(2)(o), V=3504(1) A(3); triclinic system; space group: P1. EPR spectra of these solids are identical and show strong antiferromagnetic coupling between the copper atoms, similar to the spectrum obtained for [Cu(2)(II)(niflumate)(4)(DMSO)(2)]. The [Cu(2)(II)(niflumate)(4)(H(2)O)(2)], [Cu(2)(II)(niflumate)(4)(H(2)O)(2)].4DMA, [Cu(2)(II)(niflumate)(4)(H(2)O)(2)].4DMF, [Cu(2)(II)(niflumate)(4)(DMF)(2)], and[Cu(2)(II)(niflumate)(4)(DMSO)(2)] evidenced protection against maximal electroshock-induced seizures and Psychomotor seizures at various times after treatment, consistent with the well known antiinflammatory activities of Cu chelates, but failed to protect against Metrazol-induced seizures while evidencing some Rotorod Toxicity consistent with a mechanism of action involving sedative activity.
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PMID:Low-temperature (180 K) crystal structures of tetrakis-mu-(niflumato)di(aqua)dicopper(II) N,N-dimethylformamide and N,N-dimethylacetamide solvates, their EPR properties, and anticonvulsant activities of these and other ternary binuclear copper(II)niflumate complexes. 1562 Dec 67

We describe a child with classical Menkes disease with a novel ATP7A mutation, intractable seizures, severe hypotonia and developmental delay, hypopigmentation of the skin and hair, and failure to thrive, who was treated with daily subcutaneous copper histidine injections for 2(1/2) years, beginning at 15 months of age. He became seizure-free and pigmentation of his skin and hair darkened, but he continued to have severe developmental delays. His condition remains stable 8 months after stopping treatment. We review the ethical aspects of offering copper treatment for Menkes disease infants diagnosed after neurological symptoms become manifest. These include (1) the prospect for any benefits, (2) the potential risks and discomforts, (3) the parents' wishes with respect to treatment, (4) the family's understanding of the treatment's potential futility, (5) the family's understanding of the investigational nature of this treatment, (6) the potential for treatment to have an adverse impact on unaffected family members, (7) whether the ultimate decision regarding treatment should rest with health care providers or with the patient's parents, and (8) the duration of treatment. The ethical issues encountered in providing possibly futile treatment in this difficult disorder seem relevant to other pediatric medical conditions as well.
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PMID:Copper-replacement treatment for symptomatic Menkes disease: ethical considerations. 1609 18

The genetically programmed form of neuronal death known as apoptosis plays a role in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease. Apoptosis is also responsible for neuronal death after traumatic brain and spinal cord injury, stroke, and seizures. The cognitive and behavioral consequences of all of these disorders can be devastating. Unfortunately the mechanisms that regulate neuronal apoptosis are complex. However, it is this very complexity that provides us with a wide array of potential targets for the development of anti-apoptotic strategies. Thus, our lab is currently exploring the molecular and cellular mechanisms responsible for neuronal apoptosis, with a particular focus on the role of the metals copper, zinc, and iron. Each of these metals is essential for normal central nervous system (CNS) development and function. However, imbalances, either excess or deficiency, can result in neuronal apoptosis. In this review, we show the relationship between these metals in neurodegenerative disorders and CNS injury, and the mechanisms that govern neuronal survival and apoptosis.
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PMID:Trace metal regulation of neuronal apoptosis: from genes to behavior. 1612 8

In these experiments we have tested the effect of bis(acetato)tetrakis (imidazole) copper(II) on the release and uptake of 14C-GABA and 3H-glutamate from brain slices and brain cortical synaptosomes. Cu(OAc)2(Im)4 in concentrations ranging from 1 to 100 microM has increased the release of GABA and glutamate from brain slices and synaptosomal preparations in a dose-related manner when the effect on GABA release is two-fold greater than glutamate and 10-fold greater than alanine. Pretreatment with a GABA uptake inhibitor such as 1-2 mM nipecotic acid has no effect on 14C-GABA release, whereas hydroxy aspartate, the glutamate uptake inhibitor, has elevated the stimulated release of glutamate. Copper(II) chloride, the inorganic form of copper, had no significant effect either on GABA release or on glutamate release. The stimulated release of exogenous GABA and glutamate was Ca2+-dependent, because it was inhibited by EGTA, and neuronal, because it was blocked by tetrodotoxin. The recent results can explain the anticonvulsant activity of Cu(OAc)2(Im)4 against strychnine-induced seizures by increasing the net release of GABA from cortical neurons.
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PMID:Stimulated release of exogenous GABA and glutamate from cerebral cortical synaptosomes and brain slices by bis(acetato)tetrakis(imidazole) copper(II) complex. 1632 73

Copper and zinc are trace nutrients essential for normal brain function, yet an excess of these elements can be toxic. It is important therefore that these metals be closely regulated. We recently conducted a quantitative trait loci (QTL) analysis to identify chromosomal regions in the mouse containing possible regulatory genes. The animals came from 15 strains of the BXD/Ty recombinant inbred (RI) strain panel and the brain regions analyzed were frontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. Several QTL were identified for copper and/or zinc, most notably on chromosomes 1, 8, 16 and 17. Genetic correlational analysis also revealed associations between these metals and dopamine, cocaine responses, saccharine preference, immune response and seizure susceptibility. Notably, the QTL on chromosome 17 is also associated with seizure susceptibility and contains the histocompatibility H2 complex. This work shows that regulation of zinc and copper is under polygenic influence and is intimately related to CNS function. Future work will reveal genes underlying the QTL and how they interact with other genes and the environment. More importantly, revelation of the genetic underpinnings of copper and zinc brain homeostasis will aid our understanding of neurological diseases that are related to copper and zinc imbalance.
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PMID:Quantitative genetic analysis of brain copper and zinc in BXD recombinant inbred mice. 1691 Jan 73

Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia, and failure to thrive, is due to inherited loss-of-function mutations in the gene encoding a copper-transporting ATPase (Atp7a) on the X chromosome. Although affected patients exhibit signs and symptoms of copper deficiency, the mechanisms resulting in neurologic disease remain unknown. We recently discovered that Atp7a is required for the production of an NMDA receptor-dependent releasable copper pool within hippocampal neurons, a finding that suggests a role for copper in activity-dependent modulation of synaptic activity. In support of this hypothesis, we now demonstrate that copper chelation exacerbates NMDA-mediated excitotoxic cell death in primary hippocampal neurons, whereas the addition of copper is specifically protective and results in a significant decrease in cytoplasmic Ca(2+) levels after NMDA receptor activation. Consistent with the known neuroprotective effect of NMDA receptor nitrosylation, we show here that this protective effect of copper depends on endogenous nitric oxide production in hippocampal neurons, demonstrating in vivo links among neuroprotection, copper metabolism, and nitrosylation. Atp7a is required for these copper-dependent effects: Hippocampal neurons isolated from newborn Mo(br) mice reveal a marked sensitivity to endogenous glutamate-mediated NMDA receptor-dependent excitotoxicity in vitro, and mild hypoxic/ischemic insult to these mice in vivo results in significantly increased caspase 3 activation and neuronal injury. Taken together, these data reveal a unique connection between copper homeostasis and NMDA receptor activity that is of broad relevance to the processes of synaptic plasticity and excitotoxic cell death.
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PMID:Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity. 1700 21


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