title: Rolipram does not normalize very long-chain fatty acid levels in adrenoleukodystrophy protein-deficient fibroblasts and mice.
abstract: In its severe form, X-linked adrenoleukodystrophy (X-ALD) is a lethal neurodegenerative disorder with inflammatory demyelination, in which defective peroxisomal beta-oxidation causes accumulation of very long-chain fatty acids (VLCFA) in tissues and plasma, in particular in the nervous system and adrenal glands. Recently, several drugs have been reported to reduce VLCFA in cultured human fibroblasts of X-ALD patients, and therefore to be potential candidates for novel therapeutic treatments in X-ALD. Among the most promising of these substances is the antidepressant rolipram, because of favourable adverse event profile in clinical studies and its additionally reported anti-inflammatory action. To further elucidate the effects of rolipram on peroxisomal beta-oxidation and VLCFA accumulation, we administered rolipram orally in the diet to ALD protein-deficient mice and ALD protein-deficient cultured human and mouse fibroblasts and assayed the accumulation of VLCFA. In contrast to the previously reported reduction of VLCFA, our data did not demonstrate a decrease in VLCFA content either in vivo or in vitro. NMR spectroscopic analysis verified the structural integrity and purity of the rolipram used here, thus excluding inauthenticity as a reason for the discrepancy. We therefore suggest that rolipram should be excluded from the current list of potential therapeutic agents for X-ALD.
authors.affiliation: Division of Neuroimmunology, Brain Research Institute, University of Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Netik
authors.forename: A
authors.initials: A
authors.lastname: Hobel
authors.forename: H
authors.initials: H
authors.lastname: Rauschka
authors.forename: B
authors.initials: B
authors.lastname: Molzer
authors.forename: S
authors.initials: S
authors.lastname: Forss-Petter
authors.forename: J
authors.initials: J
authors.lastname: Berger
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D000326:Adrenoleukodystrophy / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D002461:Cell Line, Transformed; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology* / Q000627:therapeutic use; D013539:Simian virus 40
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids; D008565:Membrane Proteins; D010726:Phosphodiesterase Inhibitors; D020889:Rolipram