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Cholesterol-independent neuroprotective and neurotoxic activities of statins: perspectives for statin use in alzheimer disease and other age-related neurodegenerative disorders

Contents lists available at Pharmacological Research Cholesterol-independent neuroprotective and neurotoxic activities of statins: Perspectives for statin use in Alzheimer disease and other age-related D. Allan Butterfield , Eugenio Barone , Cesare Mancuso a Department of Chemistry, Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506, USA b Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA c Institute of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito 1, 00168 Rome, Italy Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum choles- Received 13 April 2011 terol levels, also have been proposed for use in neurodegenerative conditions, including Alzheimer Accepted 14 April 2011 disease. However, it is not clear that the purported effectiveness of statins in neurodegenerative dis- orders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles.
Moreover, it is becoming more apparent with additional studies that statins can have deleterious effects Pleiotropic functions in preclinical studies and lack effectiveness in various recent clinical trials.
Alzheimer disease This perspective paper outlines pros and cons of the use of statins in neurodegenerative disorders, with Statins as Janus molecules particular emphasis on Alzheimer disease.
2011 Elsevier Ltd. All rights reserved.
1. Basic pharmacology of statins
in HDL-cholesterol, put these drugs in the arena of cardiovascular agents, due to their ability to counteract hyperlipidemias, the major Statins are a family of drugs with pleiotropic functions. To cause of atherosclerosis which, in turn, is a common pathogenetic this class belong 8 drugs: mevastatin and lovastatin, which were mechanism for coronary artery disease, ischemic cerebrovascular the first developed and studied in humans; pravastatin and sim- disease and peripheral vascular disease vastatin, which can be considered as derivatives of the parental Although statins share the same main mechanism of action, lovastatin; and atorvastatin, fluvastatin, rosuvastatin and pitavas- their pharmacokinetic profile is quite different All statins tatin, which are distinct synthetic compounds Due to their are well absorbed by the intestine when given by orally, even main mechanism of action, namely the inhibition of the hydroxyl- though they undergo marked first-pass effects by the liver, which methyl-glutaryl-CoA (HMG-CoA) reductase, statins are widely used reduces the systemic biovailability (5–30%) the excep- for the treatment of dyslipidemias By inhibiting HMG-CoA tion of simvastatin and lovastatim, which are pro-drugs and reductase, statins block the conversion of HMG-CoA into meval- require hepatic activation, other statins are administered as ␤- onate, the first step in cholesterol biosynthesis As a result hydroxy-acids. Upon administration, statins reach peak plasma of statin administration, low-density lipoprotein (LDL)-cholesterol concentration, ranging from 10 to 448 ng/ml, within 0.5–4 h. In the synthesis decreases in hepatocytes and this reflects a reduced plasma, statins are bound to albumin (43–99%) and this binding cholesterol blood level. In addition to this effect, statins have been accounts for their variable half-life Atorvastatin and rosu- shown to reduce triglyceride and increase HDL-cholesterol plasma vastatin are the statins with the longest half-life (15–30 and levels. Taken together, the composite effect of statins in reduc- 20.8 h, respectively), whereas fluvastatin, lovastatin, pravastatin ing triglycerides and LDL-cholesterol, coupled with the increase and simvastatin have half-lives around 0.5–3 h statins are metabolized by the liver through the isoforms 3A4 (atorvastatin, lovastatin and simvastatin) and 2C9 (fluvastatin and rosuvastatin) of the cytochrome-P-450 (CYP) system, whereas pravastatin under- 夽 Perspective articles contain the personal views of the authors who, as experts, goes sulfation. The primary route of elimination is fecal, and only a reflect on the direction of future research in their field.
minor fraction of statins is eliminated via urine Corresponding author at: Department of Chemistry, Center of Membrane Sci- The main adverse effects of statins are hepatotoxicity and ences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY myopathy. A transient elevation of serum transaminases (up to 3- 40506, USA. Tel.: +1 859 257 3184; fax: +1 859 257 5876.
E-mail address: (D.A. Butterfield).
times the baseline value) is a common outcome of statin therapy 1043-6618/$ – see front matter 2011 Elsevier Ltd. All rights reserved.
D.A. Butterfield et al. / Pharmacological Research 64 (2011) 180–186 Pharmacokinetic parameters of statins.
D.A. Butterfield et al. / Pharmacological Research 64 (2011) 180–186 Table 1 (Continued) Adapted from Refs. B, bioavailability; Cmax, peak plasma level; E, excretion; L, lipophilicity; M, metabolism; Pb, protein binding; T1/2, half life; Tmax, time to reach peak plasma concentration.
However, the incidence of this side effect is low and dose- of all, statins exhibit inhibitory effects on small G proteins, by alter- dependent and does not imply the contraindication of statins in ing the isoprenylation process Neuroprotective effects of individuals with concomitant liver diseases such as hepatitis C simvastatin for example, include the improvement of behavioral Myalgia is often associated with statin use and is paralleled by an function associated with an inhibition of Rho-associated kinase increase in plasma creatine kinase up to 10 times (ROCK) in a rabbit model of ischemic stroke and the pre- sis is quite rare, and the risk to develop this side effect of statins is vention of dopaminergic neuronal loss trough the inhibition of correlated to the dose and plasma concentration 30 cases p21(ras)-induced NF-kappaB increase in a mouse model of Parkin- of serious hepatic failure and 42 cases of death due to rhabdomy- son's disease Conversely, prolonged treatment of olisis associated with statin administration were reported to the human mature oligodentrocyte with simvastatin was associated FDA over the last 15 years order to reduce the incidence of with cell death Moreover, evidence for decreased hepatotoxicity and myopathy, statins should not be associated with learning and memory following long-term simvastatin treatment inhibitors of CYP3A4 such as azole antifungals, erythromycin, rito- exists Lovastatin, was effective to ameliorate experimen- navir and grapefruit juice. Also the association statins and fibrates tal autoimmune encephalomyelitis by reducing the activities of should be avoided, in particular gemfibrozil Rho/Ras family GTPase in glial cells In contrast, the same drugs efficiently inhibited Ras-induced ERK1/2 phosphorylation in 2. Pleiotropic effects of statins
rat brain neuroblasts as well as geranylgeranylation of Rho family GTPase in neurons to an increase in apotosis The debate about statin treatment regards the mechanism of and tau phosphorylation, respectively Noting that action by which statins mediate their potentially beneficial effects.
inflammatory processes occur in several neurodegenerative disor- In particular, are these benefits due to the well known ability of ders, such as Alzheimer disease, statin-mediated inhibition of Rho statins to lower cholesterol or to their so called pleiotropic effects GTPases seems to attenuate beta-amyloid (A␤) peptide-stimulated Statins can modulate several cellular pathways, indepen- inflammation in microglia Moreover, mevastatin and lovas- dent of their ability to inhibit HMG-CoA reductase. These processes tatin were reported to, respectively, decrease and increase neurite include isoprenylation and myelination, modulation of immune outgrowth in different strains of PC12 cells through different mech- response, and effects on oxidative and nitrosative stress levels.
Downstream consequences of reduced isoprenoid synthe- sis may include changes in vascular function, modulation of 2.1. Isoprenylation the insulin/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway possibly a reduction in reactive oxygen The isoprenylation process is significantly and directly affected species production statin-mediated reduction of protein by HMG-CoA reductase activity. Through the inhibition of HMG- isoprenylation could have widespread effects on protein transport, CoA reductase activity, statins reduce the formation of l-mevalonic trafficking, mRNA stability and gene transcription the acid and subsequent prevention of isoprenoid synthesis clinical significance of the results discussed above is debatable. The seventh step of the cholesterol synthesis yields farnesyl pyrophos- question whether inhibition of isoprenylation process occurs in the phate (FPP), which can be converted into squalene and hence to brain therefore remains open.
cholesterol, but is also used for the production of geranylgeranyl pyrophosphate (GGPP). Both FPP and GGPP are required to enable proper subcellular localization and trafficking of intracellular pro- teins FPP is also the substrate for production of coenzyme Although initially statins were thought to be beneficial for Q10 (CoQ10) and dolichol Coenzyme Q10 is an antioxidant, myelination and proposed as a treatment for multiple sclerosis and dolichol may function as a radical scavenger. Of these two, only CoQ10 has been seriously studied in relation to statin treat- ment: statins decrease CoQ10 levels in plasma and tissue, which may be responsible for several of statins' side effects syl pyrophosphate and GGPP on the other hand have received much attention as possible mediators of the non-cholesterol-dependent effects of statins particular, small GTP-binding proteins, including members of the Ras and Rho GTPase family, require prenylation post-translational modifications to function as mod- ulators of the actin cytoskeleton and to participate in intracellular signaling depending on statin type, length of treat- Fig. 1. Cholesterol-independent neuroprotective versus neurotoxic effects of
ment, and cellular type the final outcome could be different. First statins. Black arrows: stimulation; dotted lines: inhibition.
D.A. Butterfield et al. / Pharmacological Research 64 (2011) 180–186 (MS), a demyelinating condition benefits are being and other reactive oxidants, which can have negative effects on re-evaluated, since contradictory results have been described. As endothelial cells for isoprenylation processes, both in vitro and in vivo results sug- gest that statin- and cell type play pivotal roles in the final outcome.
2.5. Cholesterol oxidation products Simvastatin treatment had a detrimental effect on oligodentrocyte outgrowth, a key step in the re(myelination) process Statin effects on oxidative stress should take into account ularly in the early myelination stage Interestingly, cholesterol reduction, considering that cholesterol itself, can be simvastatin and lovastatin had an opposite effect on the myelin oxidized with likely loss of its functions. Cholesterol can undergo basic protein (MBP), since simvastatin treatment greatly increased oxidative modifications at least by two mechanisms: a direct rad- the densities of MBP in oligodentrocytes of neonatal rats after ical attack involving ROS or RNS (non-enzymatic mechanism), or hypoxia–ischemia damage lovastatin reduced MBP by the activity of a specific enzymes (enzymatic mechanism). This expression in primary oligodentrocytes, probably by impairment leads to the formation of cholesterol oxidation products, i.e., oxys- of the isoprenylation process terols. These latter moieties are major regulators of cholesterol homeostasis in the central nervous system Among oxys- 2.3. Immunomodulatory effects terols, 7-ketocholesterol (7-K) and 25-hydroxycholesterol (25-OH) have been shown to cause apoptotic neuronal death by inducing The immune response plays a role in neurodegeneration, not mitochondrial dysfunction Ca2+ influx and perturbation of only in MS, but also in Alzheimer and Parkinson diseases intracellular ionic homeostasis Statins may have immunomodulatory effects, which also could be Although some evidence suggests the importance of choles- mediated through reduced protein prenylation, although, so far, terol oxidation products both as in vivo markers of oxidative stress no singular mechanism has been proposed vitro, lovastatin well as for their pro-oxidant features prevents expression of TNF and IL-1␤ prubocol reduces studies exist regarding the effect of statins on cholesterol oxidation glial activation In addition, microglial cultures exposed to products in vivo group showed that atorvastatin can atorvastatin and simvastatin showed reduced levels of the pro- have two independent effects on cholesterol and cholesterol oxida- inflammatory cytokine, IL-6 However, the effects of tion products, since a reduction of cholesterol was not associated statins on the immune cells of the CNS, the microglia, have received with a reduction of 7-K or 25-OH and vice versa. In fact, the levels of little attention and need to be further explored.
both 7-K and 25-OH were reduced in brain, while 7-K levels were significantly increased in serum in dogs receiving atorvastatin 2.4. Oxidative and nitrosative stress These results, together with those showing a marked peripheral Another intriguing aspect related to the pleiotropic effects reduction of CoQ10 after long-term treatment with statins, suggest induced by statin treatment regards the modulation of oxida- that statins can exert antioxidant/pro-oxidant effects depending on tive stress-related modifications that occur in neurodegenerative the site of action and on the mechanisms modulated. Due to dura- disorders Statins can inhibit endothelial O 2–• formation by tion of statin treatment, it would be interesting to carry out in vivo preventing the isoprenylation of p21 Rac, which is critical for the studies to analyze in the brain changes that occur to cholesterol oxi- assembly of NADPH oxidase after activation of PKC In dation products and CoQ10. Can these changes to be correlated? Do addition, SOD3 activity was more than doubled by simvastatin, and statins decrease CoQ10 in the brain? Is reduction/increase of CoQ10 simvastatin treatment also increased the number of functionally associated with different levels of oxysterols? active endothelial progenitor cells Moreover, statins We believe that more detailed research into the pharmacology increase the expression of endothelial nitric oxide synthase (eNOS) of statins, particularly the concentrations achieved in the CNS and by inhibition of Rho isoprenylation statins can also directly the level at which they block the production of cholesterol and they activate eNOS via post-translational mechanisms involving activa- modulate all the above pathways, may prove beneficial to better tion of the PI3K/Akt pathway Statins showed positive understating of the potential use of statins in neurodegenerative effects against Alzheimer-relevant A␤-induced oxidative stress in mice models of AD well as a reduction in CSF tau protein phosphorylation in humans although statin treat- ment appears to provide greater benefits, it is difficult to tease out 3. Statins and dementia: suggestion to use evidence-based
whether the benefits are really due to lower cholesterol levels or to medicine as a basis of future studies
statin pleiotropy treatment was neuroprotective against cell degeneration induced by A␤(1-40), reducing inflam- Although the several lines of preclinical evidence showed neuro- matory and oxidative responses and increasing the expression of protective effects of statins in ameliorating cognitive dysfunction, glutamatergic transporters et al. (2010) showed that clinical data largely have not supported such a conclusion. In addi- long-term atorvastatin did not affect A␤ levels, despite a significant tion, clinical studies show opposite results depending whether or reduction in ␤-secretase 1 (BACE1) protein levels and activity in the not they were observational studies or randomized clinical trials brain of aged beagles we found that although no change in A␤ levels occur, long-term atorvastatin significantly reduced Early clinical data based on cohort and case-control studies, lipoperoxidation, protein oxidation and nitration, and increased demonstrated that statins reduced the risk to develop dementia, GSH levels in parietal cortex of the same animals including Alzheimer disease (AD), and this protective effect was This effect was cholesterol- and A␤-independent and specific for maintained over a 6 year follow-up period findings brain side effects of long-term statin treatment were recently contradicted by Benito-Leon et al., who demon- include a decrease in CoQ10 levels resulting in energy metabolism strated that statins did not improve cognition in elderly subjects impairment in heart, skeletal muscle, and liver Sup- with a median age of 72 years results, were obtained plementation of the diet with CoQ10 was reported to reverse many in a large cohort study, which involved more than 2 million sub- of these alterations the same time, the effect of lipophilic jects aged 30–84 years of whom 10.7% received statins statins can result in elevated tissue oxidative stress through NO a weak improvement in cognitive performance (evaluated by the reacting with metabolically derived O2–• to form peroxynitrite Hopkins word list and Rivermead paragraph) was found in individ- D.A. Butterfield et al. / Pharmacological Research 64 (2011) 180–186 uals with mild cognitive impairment, arguably the earliest form of which statins had a major effect on cognitive functions recruited AD, treated with statins individuals aged 68–74 years it is possi- In order to confirm these epidemiological studies, some RCT ble that 68–74 years of age should not be considered as a "thresh- were performed with comparable outcomes. The PROSPER study, old" or upper limit for statin efficacy in preventing dementia, since which involved about 6000 people aged 70–82 years, demonstrated both the LEADe and PROSPER studies enrolled individuals within that pravastatin (40 mg/day) did not improve cognitive function the same range of age, and these studies failed to demonstrate any over a follow-up of 3 years The LEADe study tested the beneficial effect of statins in people with AD. Subjects aged 80 or hypothesis that atorvastatin (80 mg/day) over 72 weeks delayed older also did not have any beneficial effects from statins cognitive decline in subjects with mild-moderate AD. The results of this study, did not support any significant positive effect of ator- 4.3. Cholesterol blood levels at baseline vastatin on cognitive or global functions in patients receiving the statin compared to those with placebo 2008 the CLASP study An important issue to consider when giving a statin is the was designed to evaluate the neuroprotective role of simvastatin degree of reduction of cholesterol levels in serum. Recalling that (20–40 mg/day) for 18 months in mild–moderate AD patients cholesterol is a main component of cell membranes, in particu- The results of this trial, not yet published, failed to demonstrate a lar myelin cholesterol blood levels fall due to uncontrolled therapeutic role for simvastatin the other hand, the ADCLT therapy with lipid lowering agents, nervous function would also trial demonstrated that atorvastatin (80 mg/day) for 1 year exhib- decrease. An increase in total blood cholesterol levels at midlife ited a significant positive effect on cognitive performance after 6 age was associated with an increased risk to develop AD months of therapy compared with placebo. However, this beneficial As summarized by McGuinnes et al. in two recent meta-analyses, effect was narrowed to individuals who matched restricted criteria, AD subjects recruited for large clinical trials had serum LDL choles- such as a higher MMSE score at the baseline, total cholesterol levels terol around 131–147 mg/dL same authors reported that higher than 200 mg/dl and the presence of an apolipoprotein-E-4 after the administration of atorvastatin (80 mg) for 52 weeks or allele With the purpose to put together and analyze the simvastatin (40 mg) for 26 weeks a reduction of LDL-cholesterol of results from all the RCT trials about statins and dementia, McGuin- 50–54% in AD patients was observed values of LDL- ness et al. performed a meta-analysis and concluded that there is cholesterol, before and after statin treatment, are still acceptable not evidence strong enough to recommend statins for the treatment and do not imply any possible adverse effects. However, although of dementia and AD statement agrees with the guidelines there was beneficial effect of statins on LDL-cholesterol plasma lev- of the British Association for Psychopharmacology who does not els, no beneficial effect on cognitive function was observed recommend statins for the prevention or treatment of AD Even in hypercholesterolemic patients, statins did not reduce A␤ in both plasma and cerebrospinal fluid (CSF), suggesting the lack 4. Pitfalls
of any statin-mediated on A␤ deposition or clearance sidering that an excessive reduction in cholesterol plasma levels The conflicting results described above prompt the question, is not advisable, statins could not be administered to AD patients "what are the reasons why statins had such inconsistent beneficial with low cholesterol plasma levels such as those affected by liver effects in aged or demented individuals?" Even if it is not possi- failure. Evans et al. showed that in AD patients heterozygous for ble to single out the main drawback, some criticisms need to be APOE4 allele or carriers of PS1 mutations, the administration of addressed and carefully evaluated.
simvastatin or atorvastatin slightly reduced the concentration of CSF-cholesterol at 6–7 months followed by a peak at 2 years and 4.1. Ability to cross membranes a return to baseline levels after three years finding lends support to the idea that, despite the changes in plasma choles- Due to different chemical structures, different statins exhibit terol levels, only minimal changes in brain cholesterol occur after a variable degree of lipophilicity. The prodrugs simvastatin and statin therapy and, therefore, the effect on cognitive functions are lovastatin have the highest log D (index of lipophilicity), ator- independent of the "local" cholesterol metabolism.
vastatin, fluvastatin and pitavastatin an intermediate log D while pravastatin has the lowest considerations might suggest 4.4. Interaction with xenobiotics use of lipophilic statins in demented patients to increase the frac- tion that reaches the brain. However, both the LEADe and CLASP Patients with AD, as well as other types of dementia, usually trial failed to demonstrate a beneficial effects of atorvastatin and take other drugs for other age-related disorders or co-morbitites lipophilic simvastatin on cognitive function in AD subjects, con- associated with AD. As mentioned above, all statins, with the excep- sistent with those obtained in the PROSPER study performed with tion of pravastatin, are metabolized by CYP3A4 or CYP2C9, and lipophobic pravastatin. Therefore, the different degree of liposolu- their plasma levels could be reduced or increased in the case of bility likely is not the key determinant that limited effectiveness of concomitant administration of drugs that induce or inhibit these statins in these clinical trials.
CYP isoforms. Drugs used in AD, such as donepezil and galan- tamine, also are metabolized by CYP3A4 therefore, could compete with statins. As a consequence of this interaction, statin plasma levels could increase as well as the risk of side effects.
Epidemiological data demonstrate the incidence of AD increases Also, AD patients can often be supplemented with dietary products with age and doubles every 5 years after 65 years of age with 1275 including curcumin, grapefruit juice and green tea as these natu- new cases/100,000 persons/year the Western hemisphere, ral substances are widely considered as free radical scavenger and the prevalence of AD was calculated as about 1% in subjects aged therefore neuroprotective. Unfortunately, these natural substances 60–64 but increased to between 33% and 50% in people aged 85 or are inhibitors of CYP3A4 and, therefore, increase plasma concen- older this is mind, both cohort studies and RCT that trations of statins it was reported that the examined the role of statins in AD were based on populations aged concomitant assumption of simvastatin and grapefruit or green tea 65–84 years. Although the clinical studies and the meta-analysis originated rhabdomyolisis discussed above do not support an overall beneficial effect for Taken together, the results from evidence-based medicine sug- statins in dementia and AD, it is noteworthy that those studies in gest that the ideal AD subject with some possibility to have an D.A. Butterfield et al. / Pharmacological Research 64 (2011) 180–186 increased cognitive performance upon treatment with statins is [14] van der Most PJ, Dolga AM, Nijholt IM, Luiten PG, Eisel UL. Statins: mechanisms aged 65–74 years, harbors an ApoE-4 allele normocholes- of neuroprotection. Prog Neurobiol 2009;88:64–75.
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Review article: vitamin d and inflammatory bowel diseases

Alimentary Pharmacology and Therapeutics Review article: vitamin D and inflammatory bowel diseases V. P. Mouli* & A. N. Ananthakrishnan†,‡ *Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.† Harvard Medical School, Boston, Vitamin D is traditionally associated with bone metabolism. The immuno- ‡Division of Gastroenterology,

Sucht - Rauchen - NikotinsuchtMedikamentenabhängigkeit/sucht Süchtig sein heißt, dass suchterzeugende Mittel nicht mehr abgesetzt werden können, ohne psychische oder körperliche Entzugserscheinungen zu bekommen. Entzugserscheinungen können sein: Nervosität, Zittern, Schweißausbrüche, Gedankenfixation auf das Suchtmittel, Denkhemmung, Halluzinationen, Delirium, Bauchkrämpfe, Übelkeit, Brechreiz, Kreislaufzusammenbruch etc.