title: A galactose-free diet enriched in soy isoflavones and antioxidants results in delayed onset of symptoms of Krabbe disease in twitcher mice.
abstract: Krabbe disease or globoid cell leukodystrophy is an autosomal recessively inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme that catalyzes the hydrolysis of galactose from galactosylceramide and galactosylsphingosine (psychosine). Psychosine accumulation results in the loss of myelin and oligodendrocytes in the brain of Krabbe patients as well as twitcher mice (natural model of human Krabbe disease). The aim of the present research was to investigate in twitcher mice the potential role of a diet deficient in galactose enriched in soy isoflavones and a pool of antioxidants molecules, such as l-glutathione, coenzyme Q10, xanthophylls, in counteracting the toxic effects derived by psychosine accumulation. A second goal of this manuscript was to demonstrate suppression of the apoptotic effects of psychosine in cultured oligodendrocyte progenitor mice cells (OLP-II) with antioxidants. The affected twitcher mice began the milk-derivatives free diet on post-natal day 15 although they also received mother's milk until post-natal day 18. Nevertheless, average life span was increased 50%, from 32+/-2 to 48+/-3 days, onset of tremor was delayed 17 days (from 21 days in the untreated twitcher mice to 38 days in the treated affected mice) and the gait in the treated mice was normal until almost a week after the untreated animals died (38+/-1 days versus 32 days at death). Weight gain in the treated animals also progressed to 38 days compared with 22 days for the untreated affected twitcher mice. Protection of the OLP-II cells against psychosine was shown using the MTT test (the ability of the tetrazolium salt MTT to form a dark blue formazan product by mitochondrial dehydrogenase in viable cells) and assay of expression of p53 and TNF-related apoptosis-inducing ligand (TRAIL). The results showed a time-dependent and concentration-dependent decrease of OLP-II viability on exposure to psychosine and dose-dependent protection with the antioxidants xanthophylls and glutathione. They also demonstrated that psychosine-induced p53 induction of apoptosis and TNF-related apoptosis-inducing ligand receptors could be decreased by l-glutathione and xanthophylls. A dietary approach may constitute a promising clinical management of the late-infantile and juvenile forms of Krabbe leukodystrophy.
authors.affiliation: Department of Physiological Sciences, University of Catania, Catania, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pannuzzo
authors.forename: Venera
authors.initials: V
authors.lastname: Cardile
authors.forename: Elvira
authors.initials: E
authors.lastname: Costantino-Ceccarini
authors.forename: Elisa
authors.initials: E
authors.lastname: Alvares
authors.forename: Domenico
authors.initials: D
authors.lastname: Mazzone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Perciavalle
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005690:Galactose / Q000008:administration & dosage; D005978:Glutathione / Q000008:administration & dosage; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage*; D007965:Leukodystrophy, Globoid Cell / Q000178:diet therapy* / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D011609:Psychosine / Q000633:toxicity; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives; D024341:Xanthophylls / Q000008:administration & dosage
chemical_list: D000975:Antioxidants; D007529:Isoflavones; D024341:Xanthophylls; D014451:Ubiquinone; D011609:Psychosine; C024989:coenzyme Q10; D005978:Glutathione; D005690:Galactose