My favorite drug II

Back from cold and rainy refereeing, but followed by exciting 3-2 win by my son’s soccer team, in which he scored the winning goal!

New paper just out from Mark Bear’s group at MIT. They have been at the forefront of identifying pharmacological interventions in mouse models of fragile X syndrome (FXS), and this has led to several current clinical trials, with potential implications for autism, as FXS patients display a number of behavioral symptoms found in autism spectrum disorder, including seizures. Using an Fmr1 mutant (knockout) mouse model of FXS, they now report that the cholesterol lowering drug lovastatin can reduce seizures in these mice. The drug reduces both the number and severity of seizures and associated behaviors induced by a loud noise (audiogenic seizures) when injected intraperitoneally or given orally 48 hours before testing. This study did not come totally out of the blue as some prior work found that other rodent models of epilepsy can respond positively to statin drugs, although conflicting findings were also reported in these models. There is evidence that statins work in these models by reducing inflammation. How does this statin work in the FXS mice? The most obvious possibility is that its effects on fatty acids and cholesterol are responsible, but Bear and colleagues provide evidence that lovastatin reduces Ras-ERK1/2 signaling and the excessive protein synthesis found in the the FXS mice. This is relevant because other methods of reducing ERK signaling also inhibit audiogenic seizures in this model. It will next be important to assess the effects of lovastatin on other autism-related behaviors in these mice. However, the authors also point out that controlling epilepsy in FXS patients is an important goal in itself, and current treatments are not without side effects whereas lovastatin has a known safety profile and is already approved for lowering cholesterol in children.

Statins are not only effective in treating and preventing cardiac disease but they have also shown efficacy in reducing risk for Alzheimer’s disease, reducing pathology in a mouse model of Parkinson’s disease, and they not only reduce the risk of stroke but they aid in functional recovery. At least some of the beneficial effects may be due to the anti-inflammatory effects of statins, which make them all the more attractive in the context of autism. Given their strong safety profile in the many millions of people taking these drugs over decades, these are my favorite drugs.

Note: Suzanne Ayres reminded me of a point made by a recent paper reporting that red blood cells from autistic patients contain less cholesterol than controls.  While this is not the same thing as measuring cholesterol in serum, it does raise the issue of findings in Smith-LemiOpitz syndrome. This congenital disease involves a reduction in cholesterol levels that leads to malformations, many organ pathologies and some autism-like symptoms. Clearly, one does not want to lower cholesterol levels too much!

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2 Responses to My favorite drug II

  1. Reduction of inflammation seems to be a key treatment focus. Any thoughts on this paper Paul ?

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