Parkinson disease (PD) is second only to Alzheimer disease as the most common neurodegenerative disorder in humans. Despite intense investigations, no effective therapy is available to halt the progression of PD. Although statins are widely used cholesterol-lowering drugs throughout the world, recent studies suggest that these drugs modulate neurodegeneration-related signaling processes and may be beneficial for PD. Simvastatin is the most potent statin in crossing the blood-brain barrier, and this particular statin drug negatively correlates with the incidence of PD and shows efficacy in animal models of PD. However, PD mainly occurs in the aging population, who are more vulnerable to cholesterol or lipid-related disorders, raising questions whether this possible beneficial effect of statins in PD patients is cholesterol dependent or cholesterol independent. This article presents data on the therapeutic efficacy of simvastatin in a chronic MPTP model of PD, reviews recent literature, and discusses the pros and cons of statin therapy in PD.
Ago T., Nunoi H., Ito T., Sumimoto H.1999. Mechanism for phosphorylation-induced activation of the phagocyte NADPH oxidase protein p47(phox): triple replacement of serines 303, 304, and 328 with aspartates disrupts the SH3 domain-mediated intramolecular interaction in p47(phox), thereby activating the oxidase. J Biol Chem274(47):33644-53.
2.
Bar-On P., Crews L., Koob AO, Mizuno H., Adame A., Spencer B., and others.2008. Statins reduce neuronal alpha-synuclein aggregation in in vitro models of Parkinson’s disease. J Neurochem105(5):1656-67.
3.
Benner EJ, Banerjee R., Reynolds AD, Sherman S., Pisarev VM, Tsiperson V., and others.2008. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One3(1):e1376.
4.
Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V., Gorantla S., and others.2004. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A101(25):9435-40.
5.
Berthet A., Bezard E.2009. Dopamine receptors and L-dopainduced dyskinesia. Parkinsonism Relat Disord15(suppl4): S8-12.
6.
Bessler H., Djaldetti R., Salman H., Bergman M., Djaldetti M.1999. IL-1 beta, IL-2, IL-6 and TNF-alpha production by peripheral blood mononuclear cells from patients with Parkinson’s disease. Biomed Pharmacother53(3):141-5.
7.
Bilheimer DW, Grundy SM, Brown MS, Goldstein JL1983. Mevinolin stimulates receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes . Trans Assoc Am Physicians96:1-9.
8.
Bokoch GM, Knaus UG2003. NADPH oxidases: not just for leukocytes anymore!Trends Biochem Sci28(9):502-8.
9.
Bosco DA, Fowler DM, Zhang Q., Nieva J., Powers ET, Wentworth P. Jr, and others.2006. Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization . Nat Chem Biol2(5): 249-53.
10.
Brahmachari S., Pahan K.2010. Myelin basic protein priming reduces the expression of Foxp3 in T cells via nitric oxide. J Immunol184(4):1799-809.
11.
Brahmachari S., Pahan K.2009. Suppression of regulatory T cells by IL-12p40 homodimer via nitric oxide. J Immunol183(3):2045-58.
12.
Brown MS, Goldstein JL1980. Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res21(5): 505-17.
13.
Crisby M.2003. Modulation of the inflammatory process by statins. Drugs Today (Barc) 39(2):137-43.
14.
Dauer W., Kholodilov N., Vila M., Trillat AC, Goodchild R., Larsen KE, and others.2002. Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A99(22):14524-9.
15.
Dauer W., Przedborski S.2003. Parkinson’s disease: mechanisms and models. Neuron39(6):889-909.
16.
de Lau LM, Koudstaal PJ, Hofman A., Breteler MM2006. Serum cholesterol levels and the risk of Parkinson’s disease. Am J Epidemiol164(10):998-1002.
17.
Dehmer T., Lindenau J., Haid S., Dichgans J., Schulz JB2000. Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J Neurochem74(5):2213-6.
18.
Dimmeler S., Zeiher AM1999. Nitric oxide: an endothelial cell survival factor. Cell Death Differ6(10):964-8.
19.
Endo A., Kuroda M., Tsujita Y.1976. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. J Antibiot ( Tokyo) 29(12):1346-8.
20.
Endo A., Tsujita Y., Kuroda M., Tanzawa K.1977. Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Eur J Biochem77(1):31-6.
21.
Feron O., Dessy C., Desager JP, Balligand JL2001. Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation103(1):113-8.
22.
Fulton D., Gratton JP, McCabe TJ, Fontana J., Fujio Y., Walsh K., and others.1999. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature399(6736): 597-601.
23.
Gao HM, Liu B., Zhang W., Hong JS2003a. Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson’s disease. FASEB J17(13): 1954-6.
24.
Gao HM, Liu B., Zhang W., Hong JS2003b. Novel antiinflammatory therapy for Parkinson’s disease. Trends Pharmacol Sci24(8):395-401.
25.
Gerfen CR, Miyachi S., Paletzki R., Brown P.2002. D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/ MAP kinase. J Neurosci22(12):5042-54.
26.
Ghosh A., Roy A., Liu X., Kordower JH, Mufson EJ, Hartley DM, and others.2007. Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A104(47): 18754-9.
27.
Ghosh A., Roy A., Matras J., Brahmachari S., Gendelman HE, Pahan K.2009. Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson’s disease . J Neurosci29(43):13543-56.
28.
Gonzalez-Rey E., Chorny A., Fernandez-Martin A., Ganea D., Delgado M.2006. Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells. Blood107(9):3632-8.
29.
Hayashita-Kinoh H., Yamada M., Yokota T., Mizuno Y., Mochizuki H.2006. Down-regulation of alpha-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson’s disease rat model. Biochem Biophys Res Commun341(4):1088-95.
30.
Hernandez-Perera O., Perez-Sala D., Navarro-Antolin J., Sanchez-Pascuala R., Hernandez G., Diaz C., and others.1998. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest101(12):2711-9.
31.
Hu G., Antikainen R., Jousilahti P., Kivipelto M., Tuomilehto J.2008. Total cholesterol and the risk of Parkinson disease. Neurology70(21):1972-9.
32.
Huang X., Chen H., Miller WC, Mailman RB, Woodard JL, Chen PC, and others.2007. Lower low-density lipoprotein cholesterol levels are associated with Parkinson’s disease. Mov Disord22(3):377-81.
33.
Huang X., Chen PC, Poole C.2004. APOE-[epsilon]2 allele associated with higher prevalence of sporadic Parkinson disease. Neurology62(12):2198-202.
34.
Hunot S., Boissiere F., Faucheux B., Brugg B., Mouatt-Prigent A., Agid Y., and others.1996. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience72(2): 355-63.
35.
Hunot S., Brugg B., Ricard D., Michel PP, Muriel MP, Ruberg M., and others.1997. Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with Parkinson disease. Proc Natl Acad Sci U S A94(14):7531-6.
36.
Klegeris A., Giasson BI, Zhang H., Maguire J., Pelech S., McGeer PL2006. Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells. FASEB J20(12):2000-8.
37.
Koob AO, Ubhi K., Paulsson JF, Kelly J., Rockenstein E., Mante M., and others.2009. Lovastatin ameliorates alpha-synuclein accumulation and oxidation in transgenic mouse models of alpha-synucleinopathies . Exp Neurol221(2): 267-74.
38.
Kosloski LM, Ha DM, Hutter JA, Stone DK, Pichler MR, Reynolds AD, and others.2010. Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases. J Neurochem114(5):1261-76.
39.
Kreisler A., Gele P., Wiart JF, Lhermitte M., Destee A., Bordet R.2007. Lipid-lowering drugs in the MPTP mouse model of Parkinson’s disease: fenofibrate has a neuroprotective effect, whereas bezafibrate and HMG-CoA reductase inhibitors do not. Brain Res1135(1):77-84.
40.
Lo Bianco C., Ridet JL, Schneider BL, Deglon N., Aebischer P.2002. Alpha-synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci U S A99(16):10813-8.
41.
Masliah E., Rockenstein E., Veinbergs I., Mallory M., Hashimoto M., Takeda A., and others.2000. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders . Science287(5456):1265-9.
42.
Meredith GE, Totterdell S., Potashkin JA, Surmeier DJ2008. Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat Disord14(suppl 2): S112-5.
43.
Michikawa M.2003. Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimer’s disease? J Neurosci Res72(2):141-6.
44.
Muczynski KA, Ekle DM, Coder DM, Anderson SK2003. Normal human kidney HLA-DR-expressing renal microvascular endothelial cells: characterization, isolation, and regulation of MHC class II expression. J Am Soc Nephrol14(5):1336-48.
45.
Musanti R., Parati E., Lamperti E., Ghiselli G.1993. Decreased cholesterol biosynthesis in fibroblasts from patients with Parkinson disease. Biochem Med Metab Biol49(2):133-42.
46.
Mutez E., Duhamel A., Defebvre L., Bordet R., Destee A., Kreisler A.2009. Lipid-lowering drugs are associated with delayed onset and slower course of Parkinson’s disease. Pharmacol Res60(1):41-5.
47.
Olanow CW, Tatton WG1999. Etiology and pathogenesis of Parkinson’s disease . Annu Rev Neurosci22:123-44.
48.
Pahan K., Liu X., McKinney MJ, Wood C., Sheikh FG, Raymond JR2000. Expression of a dominant-negative mutant of p21(ras) inhibits induction of nitric oxide synthase and activation of nuclear factor-kappaB in primary astrocytes. J Neurochem74(6):2288-95.
49.
Pahan K., Sheikh FG, Khan M., Namboodiri AM, Singh I.1998. Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes. J Biol Chem273(5):2591-600.
50.
Pahan K., Sheikh FG, Namboodiri AM, Singh I.1997. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest100(11):2671-9.
51.
Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di Monte DA2005. Alpha-synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Neurobiol Dis20(3):898-906.
52.
Qureshi GA, Baig S., Bednar I., Sodersten P., Forsberg G., Siden A.1995. Increased cerebrospinal fluid concentration of nitrite in Parkinson’s disease. Neuroreport6(12):1642-4.
53.
Reynolds AD, Banerjee R., Liu J., Gendelman HE, Mosley RL2007. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol82(5):1083-94.
54.
Saijo K., Winner B., Carson CT, Collier JG, Boyer L., Rosenfeld MG, and others.2009. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death . Cell137(1): 47-59.
55.
Schuster S., Nadjar A., Guo JT, Li Q., Ittrich C., Hengerer B., and others.2008. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces severity of L-DOPA-induced abnormal involuntary movements in experimental Parkinson’s disease. J Neurosci28(17):4311-6.
56.
Selley ML2005. Simvastatin prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion and protein tyrosine nitration in mice. Brain Res1037(1-2): 1-6.
57.
Shavali S., Carlson EC, Swinscoe JC, Ebadi M.2004. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline, a Parkinsonism-inducing endogenous toxin, increases alpha-synuclein expression and causes nuclear damage in human dopaminergic cells. J Neurosci Res76(4):563-71.
58.
Shrivastava S., Pucadyil TJ, Paila YD, Ganguly S., Chattopadhyay A.2010. Chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin(1A) receptors. Biochemistry49(26):5426-35.
59.
Skaletz-Rorowski A., Lutchman M., Kureishi Y., Lefer DJ, Faust JR, Walsh K.2003. HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells. Cardiovasc Res57(1):253-64.
60.
Sriram K., Matheson JM, Benkovic SA, Miller DB, Luster MI, O’Callaghan JP2006. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-alpha. FASEB J20(6):670-82.
61.
Stefanis L., Larsen KE, Rideout HJ, Sulzer D., Greene LA2001. Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci21(24): 9549-60.
62.
Teismann P., Tieu K., Cohen O., Choi DK, Wu DC, Marks D., and others.2003. Pathogenic role of glial cells in Parkinson’s disease. Mov Disord18(2):121-9.
63.
Vaziri ND, Liang K.2004. Effects of HMG-CoA reductase inhibition on hepatic expression of key cholesterol-regulatory enzymes and receptors in nephrotic syndrome . Am J Nephrol24(6):606-13.
64.
Vila M., Przedborski S.2004. Genetic clues to the pathogenesis of Parkinson’s disease. Nat Med10(suppl):S58-62.
65.
Vuletic S., Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ2006. Statins of different brain penetrability differentially affect CSF PLTP activity. Dement Geriatr Cogn Disord22(5-6):392-8.
66.
Wahner AD, Bronstein JM, Bordelon YM, Ritz B.2008. Statin use and the risk of Parkinson disease. Neurology70(16,pt2): 1418-22.
67.
Wang Q., Yan J., Chen X., Li J., Yang Y., Weng J., and others.2010. Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol Apr18. [Epub ahead of print]
68.
Westin JE, Vercammen L., Strome EM, Konradi C., Cenci MA2007. Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors . Biol Psychiatry62(7):800-10.
69.
Wolozin B., Wang SW, Li NC, Lee A., Lee TA, Kazis LE2007. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med5:20.
70.
Wood WG, Eckert GP, Igbavboa U., Muller WE2010. Statins and neuroprotection: a prescription to move the field forward. Ann N Y Acad Sci1199:69-76.
71.
Wu DC, Teismann P., Tieu K., Vila M., Jackson-Lewis V., Ischiropoulos H., and others.2003. NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Proc Natl Acad Sci U S A100(10):6145-50.
72.
Yang CC, Jick SS, Jick H.2003. Lipid-lowering drugs and the risk of depression and suicidal behavior. Arch Intern Med163(16):1926-32.
73.
Young-Xu Y., Chan KA, Liao JK, Ravid S., Blatt CM2003. Long-term statin use and psychological well-being. J Am Coll Cardiol42(4):690-7.
