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)

To identify the effects of vigabatrin (VGB) on the metabolism of pyridoxal 5'-phosphate (PLP) in the seizure prone gerbil hippocampus, we conducted a chronological and comparative analysis of pyridoxal kinase (PLK) and pyridoxine-5'-phosphate oxidase (PNP oxidase) expression. In the VGB treated animals, PNP oxidase immunoreactivity was reduced, although the distribution and immunodensity of PLK were unaltered, as compared with control animals. In a Western blot study, the densities of PNP oxidase immunoreactivities in VGB treated animals were found to have decreased significantly. However, no differences in PLK immunoreactive bands were observed in controls or in VGB treated animals. By enzyme activity assay, and in contrast to PLK, the specific activity of PNP oxidase in the VGB treated gerbils was significantly reduced. In conclusion, the present data presents a piece of in vivo evidence that supports the anti-epileptic effects mediated by pyridoxamine-5'-phosphate (PMP) metabolism, and which may be helpful in the development of an anti-epileptic drug.
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PMID:Vigabatrin inhibits pyridoxine-5'-phosphate oxidase, not pyridoxal kinase in the hippocampus of seizure prone gerbils. 1456 55

The rare autosomal recessive disorder pyridoxine 5'-phosphate oxidase (PNPO) deficiency is a recently described cause of neonatal and infantile seizures. Clinical evaluation, and biochemical and genetic testing, were performed on a neonate with intractable seizures who did not respond to anticonvulsant drugs and pyridoxine. Sequencing of the PNPO gene revealed a novel homozygous c.284G>A transition in exon 3, resulting in arginine to histidine substitution and reduced activity of the PNPO mutant to 18% relative to the wild type. This finding enabled molecular prenatal diagnosis in a subsequent pregnancy, accurate genetic counseling in the large inbred family, and population screening.
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PMID:PNPO deficiency: an under diagnosed inborn error of pyridoxine metabolism. 1848 77

To comprehend the role of pyridoxal 5'-phosphate (PLP) in epilepsy or seizure, we investigated whether the expressions of two PLP synthetic enzymes (pyridoxal kinase, PLK; pyridoxine-5'-phosphate oxidase, PNPO) are altered in the hippocampus and whether changes in paired-pulse responses in the hippocampus are associated with altered PLP synthetic enzyme expressions following status epilepticus (SE). PLK and PNPO immunoreactivities were significantly increased in the rat hippocampus accompanied by reductions in paired-pulse inhibition at 1 day and 1 week after SE. Four weeks after SE, PLK and PNPO immunoreactivities in dentate granule cells were similar to those in control animals, while their immunoreactivities were markedly reduced in Cornu Ammonis 1 (CA1) pyramidal cells due to neuronal loss. Linear regression analysis identified a direct proportional relationship between PLK/PNPO immunoreactivity and normalized population spike amplitude ratio in the dentate gyrus and the CA1 region as excluded the data obtained from 4 weeks after SE. These findings indicate that the upregulation of PLK and PNPO immunoreactivities in principal neurons may not be involved in gamma-aminobutyric acid (GABA)ergic inhibition, but rather in enhanced excitability during epileptogenic periods.
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PMID:Enhanced pyridoxal 5'-phosphate synthetic enzyme immunoreactivities do not contribute to GABAergic inhibition in the rat hippocampus following pilocarpine-induced status epilepticus. 1935 91

Neonatal epileptic encephalopathy (NEE), as a result of pyridoxine 5'-phosphate oxidase (PNPO) deficiency, is a rare neural disorder characterized by intractable seizures and usually leads to early infant death. The clinical phenotypes do not respond to antiepileptic drugs but are alleviated in most cases by giving large doses of pyridoxal 5'-phosphate (PLP). PLP is the active form of vitamin B6 participating in more than 100 enzymatic pathways. One of the causes of NEE is pathogenic mutations in the gene for human PNPO (hPNPO). PNPO is a key enzyme in converting pyridoxine (PN), the common dietary form of vitamin B6, and some other B6 vitamers to PLP. More than 25 different mutations in hPNPO, which result in reduced catalytic activity, have been described for PNPO-deficiency NEE. To date, no animal model is available to test new therapeutic strategies. In this report, we describe using zebrafish with reduced activity of Pnpo as an animal model. Knocking down zPnpo resulted in developmental anomalies including brain malformation and impaired locomotor activity, similar to the clinical features of PNPO-deficiency NEE. Other anomalies include a defective circulation system. These anomalies were significantly alleviated by co-injecting either zpnpo or hPNPO mRNAs. As expected from clinical observations in humans, supplementing with PLP improved the morphological and behavioral anomalies. PN only showed marginal positive effects, and only in a few anomalies. Remarkably, pyridoxamine (PM), another dietary form of vitamin B6, showed rescue effects even at a lower concentration than PLP, presenting a possible new therapeutic treatment for PNPO-deficiency NEE. Finally, GABA, a neurotransmitter whose biosynthesis depends on a PLP-dependent enzyme, showed some positive rescue effect. These results suggest zebrafish to be a promising PNPO-deficiency model for studying PLP homeostasis and drug therapy in vivo.
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PMID:Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO Deficiency. 3161