THERAPY FOR X-ADRENOLEUKODYSTROPHY - NORMALIZATION OF VERY LONG-CHAINFATTY-ACIDS AND INHIBITION OF INDUCTION OF CYTOKINES BY CAMP

X-adrenoleukodystrophy (X-ALD) is an inherited fatty acid metabolic di sorder with secondary manifestation of neuroinflammatory disease proce ss. We report that compounds (forskolin, 8-bromo cAMP, and rolipram) t hat increase cAMP and activate protein kinase A (PKA) were found to st imulate the peroxisomal beta-oxidation of lignoceric acid (C-24:0) whe reas 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 no rmalized the level of very long chain fatty acids (VLCFA) in X-ALD cul tured skin fibroblasts. This normalization of VLCFA in X-ALD cells wit h forskolin, 8-Br cAMP or with rolipram, an inhibitor of cAMP phosphod iesterase, was realized independent of expression of mRNA or protein o f the ALD gene, suggesting that cAMP derivatives can correct the metab olic defect in X-ALD fibroblasts without involving the candidate gene for the disease. Because astrocytes and microglia in demyelinating les ions of X-ALD brain express proinflammatory cytokines such as tumor ne crosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), we examined the effect of cAMP derivatives or rolipram on lipopolysaccha ride-stimulated rat primary astrocytes and microglia and found that cA MP derivatives and rolipram inhibited the induction of TNF-alpha and I L-1 beta in both astrocytes and microglia.ir The ability of cAMP deriv atives and rolipram to block the induction of TNF-alpha and IL-1 beta in astrocytes and microglia and to normalize the fatty acid pathogen i n skin fibroblasts of x-adrenoleukodystrophy (X-ALD) clearly identify cAMP analog or rolipram as candidates for potential therapy for X-ALD patients.