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
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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.