Abstract
Statins are attracting great interest albeit with some controversy in treating certain neurodegenerative diseases such as Alzheimer disease, Parkinson disease, multiple sclerosis, ischemic stroke, and traumatic brain injury. Support for the use of statins has come from human studies and animal and cell models. Despite the intense level of interest, there is a deficiency in information on the basic pharmacokinetics and pharmacodynamics of statins in the brain. The purpose of this focused review is to examine what is known and the gaps in our knowledge on detectability of statin lactones and acids in the brain, membrane partitioning and active transport of statins across the blood–brain barrier, and statin effects on brain isoprenoid levels. Statins may be efficacious in treating certain neurodegenerative diseases. Having basic information on statin pharmacokinetics and pharmacodynamics in the brain would provide insight into specific drug targets and also provide the rationale for optimizing statins in terms of enhancing brain influx and inhibiting efflux.
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Taylor F, Ward K, Moore THM, Burke M, Smith GD, Casas JP, Ebrahim S (2012) Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 1:2–8
Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, McBride PERH, Schwartz JS, Goldberg AC, Shero ST, Gordon D, Smith SC Jr, Levy D, Watson K, Wilson PWF (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Amer College Cardiol. doi:10.1016/j.acc.2013.11.002
Hindler K, Cleeland CS, Rivera E, Collard CD (2006) The role of statins in cancer therapy. Oncologist 11:306–315
Elewa HF, El-Remessy AB, Somanath PR, Fagan SC (2010) Diverse effects of statins on angiogenesis: new therapeutic avenues. Pharmacotherapy 30:169–176
Bessoff K, Sateriale A, Lee KK, Huston CD (2013) Drug repurposing screen reveals FDA-approved inhibitors of human HMG-CoA reductase and isoprenoid synthesis that block Cryptosporidium parvum growth. Antimicrob Agents Chemother 57:1804–1814
Ibrahim NI, Mohamed N, Shuid AN (2013) Update on statins: hope for osteoporotic fracture healing treatment. Curr Drug Targets 14(13):1524–1532
van der Most PJ, Dolga AM, Nijholt IM, Luiten PGM, Eisel ULM (2009) Statins: mechanisms of neuroprotection. Prog Neurobiol 88:64–75
Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J, Deng C, Yenari MA (2011) Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol 230:27–34
Montecucco F, Quercioli A, Mirabelli-Badenier M, Viviani GL, Mach F (2012) Statins in the treatment of acute ischemic stroke. Current Pharmaceutical Biotech 13:68–76
García-Bonilla L, Campos M, Giralt D, Salat D, Chacón P, Hernández-Guillamon M, Rosell A, Montaner J (2012) Evidence for the efficacy of statins in animal stroke models: a meta-analysis. J Neurochem 122:233–243
Eckert GP, Müller WE, Wood WG (2007) Cholesterol-lowering drugs and Alzheimer’s disease. Future Lipidol 2:423–432
Catarina A, Fonseca RG, Resende R, Oliveira CR, Pereira MFC (2010) Cholesterol and statins in Alzheimer’s disease: current controversies. Exp Neurol 223:282–293
Silva T, Teixeira J, Remiao F, Borges F (2013) Alzheimer’s disease, cholesterol, and statins: the junctions of important metabolic pathways. Angewandte Chemie-Int 52:1110–1121
Wang J, Xiao Y, Luo M, Luo H (2011) Statins for multiple sclerosis. Cochrane Database of Systematic Reviews 12: Art. No.: CD008386. DOI: 10.1002/14651858.CD008386.pub3
Undela K, Gudala K, Malla S, Bansal D (2013) Statin use and risk of Parkinson’s disease: a meta-analysis of observational studies. J Neurol 260:158–165
Farooqui AA (2010) Potential neuroprotective strategies for traumatic brain injury. In: Farooqui AA (ed) Neurochemical aspects of neurotraumatic and neurodegenerative diseases. Springer, New York, pp 219–248
Loane DJ, Faden AI (2010) Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic startegies. Trends Pharmacol Sci 31:596–604
Wood WG, Eckert GP, Igbavboa U, Müller WE (2010) Statins and neuroprotection: a prescription to move the field forward. Ann NY Acad Sci 1197:1–8
Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, Schubert-Zsilavecz M, Karas M, Müller WE, Wood WG (2005) Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther 312:786–793
Bischoff H, Heller AH (1998) Preclinical and clinical pharmacology of cerivastatin. Amer J Cardiol 82:18J–25J
Thelen KM, Rentsch KM, Gutteck U, Heverin M, Olin M, Andersson U, von Eckardstein A, Bjorkhem I, Lutjohann D (2006) Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin. J Pharmacol Exp Ther 316:1146–1152
Kajinami K, Takekoshi N, Saito Y (2003) Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. Cardiovascular Drug Rev 21:199–215
Chen C, Lin J, Smolarek T, Tremaine L (2007) P-glycoprotein has differential effects on the disposition of statin acid and lactone forms in mdr1a/b knockout and wild-type mice. Drug Metab Dispos 35:1725–1729
Tang BK, Kalow W (1995) Variable activation of lovastatin by hydrolytic enzymes in human plasma and liver. Eur J Clin Pharmacol 47:449–451
Holmes RS, Cox LA, VandeBerg JL (2010) Mammalian carboxylesterase 3: comparative genomics and proteomics. Genetica 138:695–708
Wood WG, Igbavboa U, Muller WE, Eckert GP (2013) Statins, Bcl-2, and apoptosis: cell death or cell protection. Mol Neurobiol 48:308–314
Ishigami M, Honda T, Takasaki W, Ikeda T, Komai T, Ito K, Sugiyama Y (2001) A comparison of the effects of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on the CYP3A4-dependent oxidation of mexazolam in vitro. Drug Metab Dispos 29:282–288
Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang W-P, Kirchgessner TG (1999) A novel human hepatic organic anion transporting polypeptide (OATP2). J Biol Chem 274:37161–37168
Lee G, Dallas S, Hong M, Bendayan R (2013) Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev 53:569–596
Nagasawa K, Nagi K, Sumitani Y, Moriya Y, Muraki Y, Takara K, Ohnishi N, Yokoyama T, Fujimoto S (2002) Monocarboxylate transporter mediates uptake of lovastatin acid in rat cultured mesangial cells. J Pharm Sci 91:2605–2613
Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94:1–14
Wang Q, Morris ME (2007) The role of monocarboxylate transporter 2 and 4 in the transport of g-hydroxybutric acid in mammalian cells. Drug Metab Dispos 35:1393–1399
Halestrap AP, Wilson MC (2013) The monocarboxylate transporter family—role and regulation. IUBMB Life 64:109–119
Kobayashi M, Otsuka Y, Itagaki S, Hirano T, Iseki K (2006) Inhibitory effects of statins on human monocarboxylate transporter 4. Int J Pharm 317:19–25
Schachter M (2004) Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fund & Clin Pharmacol 19:117–125
Hagemeyer CE, Rosenbrock H, Ditter M, Knoth R, Volk B (2003) Predominantly neuronal expression of cytochrome P450 isoforms CYP3A11 and CYP3A13 in mouse brain. Neuroscience 117:521–529
Woodland C, Huang TT, Gryz E, Bendayan R, Fawcett JP (2008) Expression, activity and regulation of CYP3A in human and rodent brain. Drug Metab Rev 40(1):149–168
Yanagimoto T, Itoh S, Sawada M, Kamataki T (1997) Mouse cytochrome P450 (Cyp3a11): predominant expression in liver and capacity to activate aflatoxin B1. Arch Biochem Biophys 340:215–218
Vickers S, Duncan CA, Vyas KP, Kari PH, Arison B, Prakash SR, Ramjit HG, Pitzenberger SM, Stokker G, Duggan DE (1990) In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab Dispos 18:476–483
Luo G, Cunningham M, Kim S, Burn T, Lin J, Sinz M, Hamilton G, Rizzo C, Jolley S, Gilbert D, Downey A, Mudra D, Graham R, Carroll K, Xie J, Madan A, Parkinson A, Christ D, Selling B, LeCluyse E, Gan LS (2002) CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 30:795–804
Meyer RP, Gehlhaus M, Schwab R, Bürck C, Knoth R, Hagemeyer CE (2009) Concordant up-regulation of cytochrome P450 Cyp3a11, testosterone oxidation and androgen receptor expression in mouse brain after xenobiotic treatment. J Neurochem 109:670–681
Sharom FJ (2011) The P-glycoprotein multidrug transporter. Essays Biochem 50:161–178
Bogman K, Peyer A-K, Török M, Küsters E, Drewe J (2001) HMG-CoA reductase inhibitors and P-glycoprotein modulation. Br J Pharmacol 132:1183–1192
Hirrlinger J, Konig J, Dringen R (2002) Expression of mRNAs of multidrug resistance proteins (Mrps) in cultured rat astrocytes, oligodendrocytes, microglial cells and neurons. J Neurochem 82:716–729
Sun H, Dai H, Shaik N, Elmquist WF (2003) Drug efflux transporters in the CNS. Adv Drug Deliv Rev 55:83–105
Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, Xu JJ, Smolarek TA (2005) Differential interaction of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos 33:537–546
Cole SL, Vassar R (2006) Isoprenoids and Alzheimer’s disease: a complex relationship. Neurobiol Dis 22:209–222
Hooff GP, Wood WG, Müller WE, Eckert GP (2010) Isopernoids, small GTPases and Alzheimer’s disease. Biochim Biophys Acta 1801:896–905
Li L, Zhang W, Cheng S, Cao D (2012) Isoprenoids and related pharmacological interventions: potential application in Alzheimer’s disease. Mol Neurobiol 46:64–77
Tong H, Holstein SA, Hohl RJ (2005) Simultaneous determination of farnesyl and geranylgeranyl pyrophosphate levels in cultured cells. Anal Biochem 336:51–59
Tong H, Wiemer AJ, Neighbors JD, Hohl RJ (2008) Quantitative determination of farnesyl and geranylgeranyl diphosphate levels in mammalian tissue. Anal Biochem 378:138–143
Hooff GP, Volmer DA, Wood WG, Müller WE, Eckert GP (2008) Isoprenoid quantitation in human brain tissue: a validated HPLC-fluorescence detection method for endogenous farnesyl- (FPP) and geranylgeranylpyrophosphate (GGPP). Anal Bioanal Chem 392:673–680
Gelb MH, Brunsveld L, Hrycyna CA, Michaelis S, Tamanoi F, Van Voorhis WC, Waldmann H (2006) Therapeutic intervention based on protein prenylation and associated modifications. Nat Chem Biol 2:518–528
Franke C, Nöldner M, Abdel-Kader R, Johnson-Anuna LN, Wood WG, Müller WE, Eckert GP (2007) Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment. Neurobiol Dis 25:438–445
Eckert GP, Hooff GP, Strandjord DM, Igbavboa U, Volmer DA, Müller WE, Wood WG (2009) Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients. Neurobiol Dis 35:251–257
Rip JW, Rupar CA, Ravi K, Carroll KK (1985) Distribution, metabolism and function of dolichol and polyprenols. Prog Lipid Res 24:269–309
Wolfe LS, Ng Ying Kin NM, Palo J, Bergeron C, Kotila M, Varonen S (1985) Dolichols are elevated in brain tissue from Alzheimer’s disease, but not in urinary sediment from Alzheimer’s disease and Down’s syndrome. Neurochem Pathol 3:213–221
Ng Ying Kin NM, Palo J, Haltia M, Wolfe LS (1983) High levels of brain dolichols in neuronal ceroid-lipofuscinosis and senescence. J Neurochem 40:1465–1473
Pappu AS, Connor WE, Merkens LS, Jordan JM, Penfield JA, Illingworth DR, Steiner RD (2006) Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol. J Lipid Res 47:2789–2798
Wood WG, Sun GY, Schroeder F (1989) Membrane properties of dolichol in different age groups of mice. Chem Phys Lipids 51:219–226
Morris G, Anderson G, Berk M, Maes M (2013) Coenzyme Q10 depletion in medical and neuropsychiatric disorders: potential repercussions and therapeutic implications. Mol Neurobiol 883:903
Löw P, Andersson M, Edlund C, Dallner G (1992) Effects of mevinolin treatment on tissue dolichol and ubiquinone levels in the rat. Biochim Biophys Acta 1165:102–109
Appelkvist EL, Edlund C, Löw P, Schedin S, Dallner G (1993) Effects of inhibitors of hydroxymethylglutaryl coenzyme A reductase on coenzyme Q and dolichol biosynthesis. Clin Investig 71:S97–102
Martin SB, Cenini G, Barone E, Dowling LS, Mancuso CA, Butterfield DA, Murphy MP, Head E (2011) Coenzyme Q10 and cognition in atorvastatin treated dogs. Neurosci Lett 501:92–95
Johnson-Anuna LN, Eckert GP, Franke C, Igbavboa U, Müller WE, Wood WG (2007) Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein. J Neurochem 101:77–86
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This work was supported in part by grants from the National Institutes of Health (AG-23524 and AG-18357).
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Wood, W.G., Mΰller, W.E. & Eckert, G.P. Statins and Neuroprotection: Basic Pharmacology Needed. Mol Neurobiol 50, 214–220 (2014). https://doi.org/10.1007/s12035-014-8647-3
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DOI: https://doi.org/10.1007/s12035-014-8647-3