Accordingly, it is possible that Glycer-AGEs, Fru-AGEs, and Glu-AGEs have unique structures, but studies involving spectroscopic and Diprenorphine biochemical analyses are required to confirm this. FRDA is the result of a GAA?TTC triplet hyper-expansion in an intron of the frataxin gene that leads to transcriptional silencing. FXN is an essential mitochondrial protein and the resultant FXN insufficiency results in progressive spinocerebellar neurodegeneration and cardiomyopathy, leading to a progressive lack of motor coordination, incapacity and eventually death, usually in early adulthood. In transformed lymphoid cell lines derived from an FRDA patient, histones H3 and H4 associated with the FXN gene are hypo-acetylated with a concomitant increase in trimethylated H3K9. These findings imply a repressed heterochromatin state and suggest that HDAC inhibitors capable of restoring acetylation to histones may have therapeutic potential. For FRDA, the effects on both H3 and H4 acetylation and FXN mRNA levels were assessed in cellular models using a variety of hydroxamic acid-based HDAC inhibitors, including valproic acid, TSA, SAHA and suberoyl bishydroxamic acid. These studies gave variable results, confounded by the cellular toxicity of these compounds. However, the pimelic diphenylamide HDAC inhibitor BML-210 was reported to increase FXN mRNA without cytotoxicity at the concentration tested. Further, application to cells of an analog of BML-210, HDACi 4b, resulted in a 2.5-fold enhancement of FXN mRNA, acetylation of H3K14, H4K5 and H4K12 in the chromatin region immediately upstream of the GAA repeats, and a 3.5-fold increase in FXN protein levels. A subsequent short pharmacodynamic study in a FRDA mouse model showed that a close analogue of HDACi 4b, the tolyl derivative compound 106, corrected the FXN deficiency. These mice carry a homozygous 230 expansion in the first intron of the mouse FXN gene. Biochemical analysis revealed that these mice carry the same heterochromatin marks, close to the GAA repeat, as those detected in patient cell lines and have mildly but Cilostamide significantly reduced FXN mRNA and protein levels; however, they show no overt phenotype. Compound 106 given at 150 mg/kg subcutaneously once daily for 3 days increased global brain tissue histone acetylation as well as histone acetylation close to the GAA repeat and restored FXN levels in the nervous system and heart. Reversion of other differentially expressed genes towards wild type levels was also observed. Compound 106 showed no apparent toxicity in this study. Recently, the long-term benefit of chronic subcutaneous administration of three pimelic o-aminobenzamide inhibitors were assessed in another mouse model of FRDA.