Simvastatin Does Not Show Same Brain Benefits for Fragile X as Lovastatin, Study Reports

Lovastatin, a medication widely prescribed for lowering cholesterol, was recently discovered to correct brain deficits linked with fragile X syndrome in mouse models of the disease. The finding prompted clinical trials to test if this statin might help people with the disease.

Other statins were also considered, including simvastatin — a lab-made derivative of lovastatin. But a new study reports that simvastatin does not show equivalent therapeutic effects, and advises against this medication as an alternative treatment for fragile X.

The findings, “Lovastatin, not simvastatin, corrects core phenotypes in the fragile X mouse model,” were published in bioRxiv.

Earlier research in mouse models of fragile X reported that lovastatin (brand names Altocor, Altoprev, Mevacor), used to lower cholesterol and reduce risk of heart attack and stroke, was able to repair key problems in the brain linked with fragile X.

The statin was able to reduce excessive protein production in the brains of treated mice, prevent epilepsy-related electrical discharges in nerve cells, and lower the incidence of experimentally-induced seizures.

The researchers also showed that the therapeutic effect of lovastatin was mediated by its ability to inhibit the activation of a molecular pathway called the MAPK-ERK1/2 signaling pathway, which they believe underlies many of the fragile X neurological defects, including excessive brain protein production.

Based on these findings, two pilot clinical trials were launched to test the safety and the effectiveness of lovastatin in easing behaviorial difficulties and on biochemical markers of fragile X.

Both studies revealed a significant improvement upon lovastatin treatment, and two other clinical trial are ongoing: a placebo-controlled Phase 4 trial (NCT02642653) testing the combination of lovastatin and a language intervention; and an open-label Phase 2 study (NCT02680379) evaluating lovastatin in combination with minocycline, a type of antibiotic.

Simvastatin (brand name Zocor) has been proposed as an alternative statin to treat fragile X due to its higher potency and facility in penetrating the brain, and also because lovastatin is not widely available worldwide, including in Europe.

For this reason, researchers set out to test if simvastatin and lovastatin were of similar benefit by comparing both statins in the same fragile X mouse model.

Treatment with lovastatin was again seen to normalized excessive protein production in the brain, specifically in the hippocampus — a brain area key to memory, learning and emotions — and to ease induced seizures.

But treatment with simvastatin failed to correct any of the these deficiencies, even when given at higher doses, the researchers note. Rather, it seemed to worsen the over-production of proteins in the brain.

Simvastatin  also failed to dampen ERK1/2 activation, “suggesting it does not share the same mechanism as lovastatin” and that “ the impact on ERK1/2 is an important factor in terms of pharmacological treatment for FX [fragile X]” the researchers said.  

“There are many reasons why statins would be an attractive option for treating neurodevelopmental disorders such as FX. They are widely prescribed worldwide for the treatment of hypercholesterolemia and coronary heart disease, and safely used for long-term treatment in children and adults,” they added.

But care should be taken when considering which statin should be tested to treat fragile X, they concluded, suggesting that “simvastatin could be similarly ineffective in FX and may not be a suitable substitute for lovastatin in further clinical trials.”