A differential effect of lovastatin versus simvastatin in neurodevelopmental disorders

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Significance statement The statin drug lovastatin normalizes excessive protein synthesis and thereby ameliorates pathological changes in animal models of Fragile X Syndrome (FX), the most commonly identified genetic cause of autism. Recently, we compared the efficacy of lovastatin to the more potent and brain-penetrant drug simvastatin for correcting phenotypes in the Fmr1-/y mouse (Muscas et al., 2019). Surprisingly, we find simvastatin worsens excessive protein synthesis and has no impact on audiogenic seizures (AGS) in Fmr1-/y mice, suggesting it does not work in a similar fashion to lovastatin. A recent commentary by Ottenhoff et al. suggests that differences in dose and/or study design might account for our results. Here we discuss the points raised by Ottenhoff et al., as well as the evidence supporting a therapeutic role for lovastatin versus simvastatin. We conclude that differences between lovastatin and simvastatin warrant careful consideration with respect to the treatment of neurodevelopmental disorders.

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