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Huntington’s disease (HD) is the most common neurodegenerative disorder with no effective cure currently available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Thus, it becomes urgent to search for new potential solutions.Sphingosine-1-phosphate (S1P) is a potent signaling lipid that regulates many of the processes essential for cellular homeostasis and viability. Recently, we provided the first evidence of aberrant metabolism of S1P across multiple disease models ranging from cells to human post-mortem brains through mouse models. Importantly, pharmacological interventions aimed at promoting S1P production by stimulating Sphingosine Kinase 1 (SPHK1) with the selective activator, K6PC-5, resulted effective in reducing apoptosis in a HD cell model and in promoting the activation of pro-survival kinases AKT and ERK in human HD iPSC-derived neurons (Di Pardo et al., 2017).In this study, we aimed to investigate whether K6PC-5 may exert therapeutic action in-vivo in R6/2 HD mouse model.Preliminary results indicate that chronic administration of 0.05 mg/kg K6PC-5 is safe and well tolerated in manifest R6/2 HD mice. The compound significantly slowed down the gradual motor deficit associated with the worsening of the disease. Further progress is needed for establishing any disease-modifying properties of the compound.Although still much remains to be investigated, our preliminary findings support the idea that K6PC-5 may represent a good candidate for the development of alternative therapeutic options, thus it deserves more attention.