Therapy for X-adrenoleukodystrophy: normalization of very long chain fatty acids and inhibition of induction of cytokines by cAMP.
X-adrenoleukodystrophy (X-ALD) is an inherited fatty acid metabolic disorder with secondary manifestation of neuroinflammatory disease process. We report that compounds (forskolin, 8-bromo cAMP, and rolipram) that increase cAMP and activate protein kinase A (PKA) were found to stimulate the peroxisomal beta-oxidation of lignoceric acid (C24:0) whereas compounds (H-89 and myristoylated PKI) that decrease cAMP and PKA activity inhibited the peroxisomal beta-oxidation of lignoceric acid in cultured skin fibroblasts from X-ALD patients. Consistent with the stimulation of beta-oxidation of lignoceric acid, activators of PKA normalized the level of very long chain fatty acids (VLCFA) in X-ALD cultured skin fibroblasts. This normalization of VLCFA in X-ALD cells with forskolin, 8-Br cAMP or with rolipram, an inhibitor of cAMP phosphodiesterase, was realized independent of expression of mRNA or protein of the ALD gene, suggesting that cAMP derivatives can correct the metabolic defect in X-ALD fibroblasts without involving the candidate gene for the disease. Because astrocytes and microglia in demyelinating lesions of X-ALD brain express proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), we examined the effect of cAMP derivatives or rolipram on lipopolysaccharide-stimulated rat primary astrocytes and microglia and found that cAMP derivatives and rolipram inhibited the induction of TNF-alpha and IL-1beta in both astrocytes and microglia. The ability of cAMP derivatives and rolipram to block the induction of TNF-alpha and IL-1beta in astrocytes and microglia and to normalize the fatty acid pathogen in skin fibroblasts of x-adrenoleukodystrophy (X-ALD) clearly identify cAMP analogs or rolipram as candidates for potential therapy for X-ALD patients.
Pahan
K
K
Department of Pediatrics, Medical University of South Carolina, Charleston 29425, USA.
Khan
M
M
Singh
I
I
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000627:therapeutic use; D000326:Adrenoleukodystrophy / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005227:Fatty Acids / Q000097:blood*; D008040:Genetic Linkage; D007375:Interleukin-1 / Q000096:biosynthesis; D007546:Isoquinolines / Q000627:therapeutic use; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones / Q000627:therapeutic use; D051381:Rats; D020889:Rolipram; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014960:X Chromosome
D016207:Cytokines; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007375:Interleukin-1; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020889:Rolipram; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C047983:1,9-dideoxyforskolin