Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, and new indications have continued to emerge for these medicines since their introduction in the late 1980s. The association between cholesterol levels, statin use, and Parkinson’s disease has been much debated in recent years, with some studies suggesting that low cholesterol levels (although not statin use) are linked to the disease, others suggesting that statin use is associated with a reduced incidence of disease, and yet others finding no effect of statin use on disease incidence.
New research by scientists at Rush University Medical Center and the University of Nebraska Medical Center now adds evidence that statins are protective by demonstrating that simvastatin can reverse the toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. MPTP causes selective dopaminergic neurotoxicity in cells of the substantia nigra, causing parkinsonism in humans and some laboratory animals. MPTP itself is not neurotoxic, but is metabolised by monoamine oxidase-B into the toxic cation, methyl-4-phenylpyridinium (MPP+). The team found that MPP+ induced activation of p21ras and nuclear factor-κB (NF-κB) in mouse microglial cells and that this effect was attenuated by simvastatin. p21ras was also found to be rapidly activated in vivo in the substantia nigra pars compacta of mice treated with MPTP. Oral administration of simvastatin reduced nigral activation of p21ras and NF-κB, inhibited expression of proinflammatory molecules, and suppressed activation of glial cells. These changes were associated with protection of dopaminergic neurones, normalized striatal neurotransmitters, and improved motor function. Pravastatin was also shown to protect dopaminergic neurons from the toxic effects of MPTP, but to a lesser extent than simvastatin. Both statins were still able to protect dopaminergic neurons when administered 2 days after treatment with MPTP, suggesting that statins may provide benefit to Parkinson’s disease patients. The use of statins would be particularly attractive because of their proven safety profile in very large patient populations.
The study is published in the current issue of the Journal of Neurosciences.