Analysis of the effects of PPAR-a-ligand fenofibrate on ABCD1-deficient mice

The X-linked adrenoleukodystrophy is a peroxisomal hereditary metabolic disease that is due to the loss of function of the peroxisomal transmembrane transporter ABCD1. We distinguish between the frequent progressive forms of infantile cerebral adrenoleukodystrophy (CALD) and the adrenomyeloneuropathy (AMN). While the AMN usually only manifests between the twentieth and thirtieth year, the CALD already in the first years of life occurs and lethal disease. Due to loss of function of the transmembrane transporter it comes to the accumulation of very long chain fatty acids and to an inflammatory demyelination in the nervous system. Mice in which the gene has been switched off ABCD1, only show a AMN-like phenotype, mice with complete loss of function of peroxisomes in myelinating cells, however, an inflammatory demyelination. It is therefore assumed as a result of ABCD1 deficiency as the cause of cerebral degeneration is a secondary, extensive loss of function of peroxisomes. In the present work, ABCD1-/ - mice treated for 30 days with 3 different concentrations of the PPARa agonist fenofibrate. The aim was to investigate the tolerability of the drug in a long-term study and the effects of fenofibrate on peroxisomal proteins in the brain. It was found that the expression of peroxisomal membrane proteins, enzymes of the peroxisomal β-oxidation, as well as anti-oxidative enzymes peroxisomal in the mouse brain can be modulated by treatment with fenofibrate. It was noticeable that the lowest administered dose of the drug often the concentration of the investigated proteins lowered, a higher concentration, however, had the opposite effect. In addition, the substance has been found in the treatment period of 30 days either on the basis of motor tests, nor by weight loss for mice as toxic. Whether the effects on the direct effects of fenofibrate, or indirectly by messengers due from peripheral tissues, have not been studied. The results presented give reason to investigate the effect of fenofibrate with regard to the treatment of leukodystrophies on.2014-07-2