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Article: Increased isoprostanoid levels in brain from murine model of Krabbe disease – Relevance of isoprostanes, dihomo-isoprostanes and neuroprostanes to disease severity

TitleIncreased isoprostanoid levels in brain from murine model of Krabbe disease – Relevance of isoprostanes, dihomo-isoprostanes and neuroprostanes to disease severity
Authors
KeywordsAdrenic acid
Isoprostanes
Krabbe disease
Leukodystrophy
Murine models
Issue Date2019
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/freeradbiomed
Citation
Free Radical Biology & Medicine, 2019, v. 139, p. 46-54 How to Cite?
AbstractKrabbe disease (KD) is a rare and devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. The disease leads to impaired myelin formation and extensive myelin damage in the brain. Oxidative stress is implicated in the pathogenesis of KD but insofar few information is available. The gray and white matter of the brain are rich in docosahexaenoic acid and adrenic acid respectively and under non-enzymatic oxidative stress, release isoprostanoids, i.e. F4-neuroprostanes (F4-NeuroPs) and F2-dihomo-isoprostanes (F2-dihomo-IsoPs). In this study, the formation of isoprostanoids in brain tissue was investigated in a well-established KD mouse model (twitcher) that recapitulates the human pathology. According to the genotype determinations, three groups of mice were selected: wild-type control mice (n = 13), heterozygotes mice (carriers of GALC mutations, n = 14) and homozygous twitcher mice (n = 13). Measurement of F2-dihomo-IsoP and F4-NeuroP levels were performed on whole brain tissue obtained at day 15 and day 35 of the life cycle. Brain isoprostanoid levels were significantly higher in the twitcher mice compared to the heterozygous and wild-type control mice. However, F2-dihomo-IsoP and F4-NeuroP levels did not differ in brain of day 15 compared to day 35 of the heterozygote mice. Interestingly, isoprostanoid levels were proportionally enhanced with disease severity (F2-dihomo-IsoPs, rho = 0.54; F4-NeuroPs, rho = 0.581; P values ≤ 0.05; n = 13). Our findings are the first to show the key role of polyunsaturated fatty acid oxidative damage to brain grey and white matter in the pathogenesis and progression of KD. This shed new insights on the biochemical indexes of KD progression, and potentially provide information for novel therapeutic targets.
Persistent Identifierhttp://hdl.handle.net/10722/271358
ISSN
2017 Impact Factor: 6.02
2015 SCImago Journal Rankings: 2.468

 

DC FieldValueLanguage
dc.contributor.authorSignorini, C-
dc.contributor.authorCardile, V-
dc.contributor.authorPannuzzo, G-
dc.contributor.authorEleonora Graziano, AC-
dc.contributor.authorDurand, T-
dc.contributor.authorGalano, JM-
dc.contributor.authorOger, C-
dc.contributor.authorLeoncini, S-
dc.contributor.authorCortelazzo, A-
dc.contributor.authorLee, JCY-
dc.contributor.authorHayek, J-
dc.contributor.authorDe Felice, C-
dc.date.accessioned2019-06-24T01:08:19Z-
dc.date.available2019-06-24T01:08:19Z-
dc.date.issued2019-
dc.identifier.citationFree Radical Biology & Medicine, 2019, v. 139, p. 46-54-
dc.identifier.issn0891-5849-
dc.identifier.urihttp://hdl.handle.net/10722/271358-
dc.description.abstractKrabbe disease (KD) is a rare and devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. The disease leads to impaired myelin formation and extensive myelin damage in the brain. Oxidative stress is implicated in the pathogenesis of KD but insofar few information is available. The gray and white matter of the brain are rich in docosahexaenoic acid and adrenic acid respectively and under non-enzymatic oxidative stress, release isoprostanoids, i.e. F4-neuroprostanes (F4-NeuroPs) and F2-dihomo-isoprostanes (F2-dihomo-IsoPs). In this study, the formation of isoprostanoids in brain tissue was investigated in a well-established KD mouse model (twitcher) that recapitulates the human pathology. According to the genotype determinations, three groups of mice were selected: wild-type control mice (n = 13), heterozygotes mice (carriers of GALC mutations, n = 14) and homozygous twitcher mice (n = 13). Measurement of F2-dihomo-IsoP and F4-NeuroP levels were performed on whole brain tissue obtained at day 15 and day 35 of the life cycle. Brain isoprostanoid levels were significantly higher in the twitcher mice compared to the heterozygous and wild-type control mice. However, F2-dihomo-IsoP and F4-NeuroP levels did not differ in brain of day 15 compared to day 35 of the heterozygote mice. Interestingly, isoprostanoid levels were proportionally enhanced with disease severity (F2-dihomo-IsoPs, rho = 0.54; F4-NeuroPs, rho = 0.581; P values ≤ 0.05; n = 13). Our findings are the first to show the key role of polyunsaturated fatty acid oxidative damage to brain grey and white matter in the pathogenesis and progression of KD. This shed new insights on the biochemical indexes of KD progression, and potentially provide information for novel therapeutic targets.-
dc.languageeng-
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/freeradbiomed-
dc.relation.ispartofFree Radical Biology & Medicine-
dc.subjectAdrenic acid-
dc.subjectIsoprostanes-
dc.subjectKrabbe disease-
dc.subjectLeukodystrophy-
dc.subjectMurine models-
dc.titleIncreased isoprostanoid levels in brain from murine model of Krabbe disease – Relevance of isoprostanes, dihomo-isoprostanes and neuroprostanes to disease severity-
dc.typeArticle-
dc.identifier.emailLee, JCY: jettylee@hku.hk-
dc.identifier.authorityLee, JCY=rp01511-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.freeradbiomed.2019.05.014-
dc.identifier.scopuseid_2-s2.0-85065907046-
dc.identifier.hkuros297954-
dc.identifier.volume139-
dc.identifier.spage46-
dc.identifier.epage54-
dc.publisher.placeUnited States-

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