Lovastatin, not simvastatin, corrects core phenotypes in the fragile X mouse model

Abstract

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. 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 (AGS). 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.

Significance Statement The statin drug lovastatin is in clinical trials for the treatment of Fragile X Syndrome (FX), and the structurally similar drug simvastatin has been proposed as a viable alternative. This study compares the efficacy of these drugs for ameliorating two major phenotypes in the FX mouse model and shows that although lovastatin is effective in correcting excessive protein synthesis and audiogenic seizures, simvastatin fails to correct either phenotype. These results suggest caution should be used when assuming simvastatin is a suitable substitute for lovastatin with respect to the treatment of FX or other neurodevelopmental disorders.