Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO Deficiency
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...
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.01086/full |
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| author | Po-Yuan Chen Hung-Chi Tu Verne Schirch Martin K. Safo Tzu-Fun Fu Tzu-Fun Fu |
| author_facet | Po-Yuan Chen Hung-Chi Tu Verne Schirch Martin K. Safo Tzu-Fun Fu Tzu-Fun Fu |
| author_sort | Po-Yuan Chen |
| collection | DOAJ |
| description | 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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| language | English |
| last_indexed | 2024-12-11T01:48:37Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-474b0acd662b4cfb8ed17af118e60f852022-12-22T01:24:49ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-09-011010.3389/fphar.2019.01086474032Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO DeficiencyPo-Yuan Chen0Hung-Chi Tu1Verne Schirch2Martin K. Safo3Tzu-Fun Fu4Tzu-Fun Fu5College of Medicine, Institute of Basic Medical Science, National Cheng Kung University, Tainan, TaiwanCollege of Medicine, Institute of Basic Medical Science, National Cheng Kung University, Tainan, TaiwanDepartment of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United StatesDepartment of Medicinal Chemistry and Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United StatesCollege of Medicine, Institute of Basic Medical Science, National Cheng Kung University, Tainan, TaiwanDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, TaiwanNeonatal 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.https://www.frontiersin.org/article/10.3389/fphar.2019.01086/fullpyridoxal 5′-phosphate (PLP)-dependent neonatal epileptic encephalopathypyridoxine 5′-phosphate oxidasepyridoxaminezebrafishanimal model |
| spellingShingle | Po-Yuan Chen Hung-Chi Tu Verne Schirch Martin K. Safo Tzu-Fun Fu Tzu-Fun Fu Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO Deficiency Frontiers in Pharmacology pyridoxal 5′-phosphate (PLP)-dependent neonatal epileptic encephalopathy pyridoxine 5′-phosphate oxidase pyridoxamine zebrafish animal model |
| title | Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO Deficiency |
| title_full | Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO Deficiency |
| title_fullStr | Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO Deficiency |
| title_full_unstemmed | Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO Deficiency |
| title_short | Pyridoxamine Supplementation Effectively Reverses the Abnormal Phenotypes of Zebrafish Larvae With PNPO Deficiency |
| title_sort | pyridoxamine supplementation effectively reverses the abnormal phenotypes of zebrafish larvae with pnpo deficiency |
| topic | pyridoxal 5′-phosphate (PLP)-dependent neonatal epileptic encephalopathy pyridoxine 5′-phosphate oxidase pyridoxamine zebrafish animal model |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.01086/full |
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