Lovastatin, not Simvastatin, Corrects Core Phenotypes in the Fragile X Mouse Model

eNeuro. 2019 Jun 12;6(3):ENEURO.0097-19.2019. doi: 10.1523/ENEURO.0097-19.2019. Print 2019 May/Jun.


The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability (ID). The therapeutic efficacy of lovastatin is being tested in clinical trials for FX; however, the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in Fmr1-/y mice versus WT littermates: excessive hippocampal protein synthesis and susceptibility to audiogenic seizures (AGSs). We find that simvastatin does not correct excessive hippocampal protein synthesis in the Fmr1-/y hippocampus at any dose tested. In fact, simvastatin significantly increases protein synthesis in both Fmr1-/y and WT. Moreover, injection of simvastatin does not reduce AGS in the Fmr1-/y mouse, while lovastatin significantly reduces AGS incidence and severity versus vehicle-treated animals. These results show that unlike lovastatin, simvastatin does not correct core phenotypes in the Fmr1-/y mouse model.

Keywords: ERK; FMR1; fragile X; lovastatin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Anticholesteremic Agents / administration & dosage*
  • Disease Models, Animal
  • Epilepsy, Reflex / complications
  • Epilepsy, Reflex / drug therapy
  • Fragile X Syndrome / complications
  • Fragile X Syndrome / drug therapy*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Lovastatin / administration & dosage*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • Protein Biosynthesis / drug effects
  • Simvastatin / administration & dosage*


  • Anticholesteremic Agents
  • Lovastatin
  • Simvastatin