Full text of DOI:10.2165/00023210-200115080-00002

CNS Drugs 2001; 15 (8) 589-596
1172-7047/01/0008-0589/$22.00/0
LEADING ARTICLE
© Adis International Limited. All rights reserved.
Do Statins Afford Neuroprotection in
Patients with Cerebral Ischaemia
and Stroke?
Carl J. Vaughan,1 Norman Delanty2 and Craig T. Basson1
1
2
Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University,
New York, New York, USA
Department of Neurosciences, Beaumont Hospital, Dublin, Ireland
Abstract
An emerging body of evidence indicates that β-hydroxy-β-methylglutaryl co-
enzyme A(HMG-CoA) reductase inhibitors, or ‘statins’, provide neuroprotection
in addition to reducing ischaemic stroke. Statins reduce the incidence of isch-
aemic stroke by stabilising atherosclerotic plaques in the precerebral vasculature
and through antithrombotic actions, and the neuroprotective effects of statins may
confer significant clinical benefit. Some of these neuroprotective effects are likely
to be cholesterol independent and mediated by the interruption of isoprenoid
biosynthesis. Therapy with statins may modulate endothelial function and pre-
serve blood flow to regions exposed to an ischaemic insult. In particular, statin-
mediated preservation of endothelial nitric oxide synthase activity in cerebral
vasculature, especially in the ischaemic penumbra, may limit neurological deficit.
Moreover, putative anti-inflammatory and antioxidant properties of statins may
confer additional neuroprotection. Further large clinical trials are necessary to
address the role of statin therapy in the primary prevention of stroke, small vessel
cerebrovascular disease and vascular dementia.
Recent clinical trials and meta-analyses of β-
adjunctive properties that may confer additional
benefit beyond the retardation of atherosclerosis.
These data indicate that statins protect neurons
from the ischaemia that occurs during stroke. In
this article, we review emerging evidence suggest-
ing that statins operate as neuroprotective agents
within the cerebral circulation and brain paren-
chyma during stroke and reperfusion. We also re-
view the anti-inflammatory, antioxidant, and endo-
thelial protective effects of statins and discuss the
hydroxy-β-methylglutaryl coenzyme A (HMG-
CoA) reductase inhibitors (‘statins’) have demon-
strated a significant reduction in ischaemic stroke
in patients with a history of coronary artery disease,
both with and without elevations of serum choles-
terol level.[1-5] The atheroma-retarding properties
of statins in both the coronary and carotid arterial
beds are well established.[6-8] However, accumulat-
ing data suggest that statins have further important

590
Vaughan et al.
putative neuroprotective properties of these com-
pounds in cerebral ischaemic syndromes.
LDL
1. Statins: Mechanism of Action
Acetyl-CoA
HMG-CoA
Mevalonate
Coated pit
HMG-CoA reductase is the rate-limiting en-
zyme for cholesterol formation in the liver and
other tissues. Expression of the reductase gene is
reduced in response to negative feedback regula-
tion by both sterol and nonsterol products of
mevalonate metabolism.[9] Through the inhibition
of HMG-CoA reductase, statins reduce hepatocyte
cholesterol content and increase expression of low
density lipoprotein (LDL) receptors which are re-
sponsible for LDL-cholesterol uptake via receptor-
mediated endocytosis (fig. 1). In addition to low-
ering intracellular levels of sterols, HMG-CoA
reductase inhibitors reduce levels of isoprenoids
which are derived from intermediates of the cho-
lesterol biosynthetic pathway. Isoprenoids post-
translationally prenylate a variety of cellular pro-
teins that play central roles in both cell growth and
signal transduction pathways. Targets include low
molecular weight guanine nucleotide binding pro-
teins (G-proteins) which have been shown to mod-
ulate signal transduction and mitogenic path-
ways.[10]
HMG-CoA R I
5-Pyrophosphomevalanate
Isopentyl pyrophosphate
3,3-Dimethyl pyrophosphate
Geranyl-geranyl pyrophosphate
Farnesyl pyrophosphate
Squalene
Isoprenoids
LDLR
Lanosterol
SREBP
Cholesterol
2. Statin Trials and Stroke
Despite the established role of cholesterol in the
pathogenesis of coronary artery disease, contro-
versy surrounds the issue of a positive association
between elevated cholesterol levels and stroke. Ep-
idemiological evidence does not demonstrate a
clear relationship between the risk of stroke and the
serum cholesterol level.[11,12] However, clinical
studies indicate that cholesterol-lowering therapy
with statins significantly reduces ischaemic stroke.
In the Cholesterol and Recurrent Events (CARE)
study, pravastatin significantly reduced the speci-
fied end-point of stroke by 31%, without increased
haemorrhagic stroke.[1] Post-hoc analysis of the
Scandinavian Simvastatin Survival Study (4S)
showed a similar reduction in stroke.[2] The Long-
Term Intervention with Pravastatin in Ischaemic
Disease (LIPID) study[3] investigators reported
LDLR
Fig. 1. Regulation of cholesterol synthesis. Inhibition of β-
hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase
reduces intracellular cholesterol levels, activating a protease
which cleaves sterol regulatory element binding proteins
(SREBPs) from the endoplasmic reticulum. SREBPs translo-
cate to the nucleus where they upregulate expression of the low
density lipoprotein (LDL) receptor (LDLR) gene. Enhanced
LDLR expression increases receptor-mediated endocytosis of
LDL and thus lowers serum LDL levels. Inhibition of HMG-CoA
reductase also reduces intracellular levels of isoprenoids which
are intermediates incholesterolbiosynthesis. Acetyl-CoA =ace-
tyl coenzyme A; HMG-CoA R I = HMG-CoA reductase inhibitor.
© Adis International Limited. All rights reserved.
CNS Drugs 2001; 15 (8)

Statins in Cerebral Ischaemia and Stroke
591
the effect of pravastatin therapy on stroke in 9014
patients with previous myocardial infarction or un-
stable angina. In this study, there were 204 strokes
in those receiving placebo and 169 strokes in
pravastatin recipients, or a 19% relative risk re-
duction in stroke with statin therapy.[3] It is note-
worthy that these secondary prevention studies
were performed predominantly in middle-aged
men with ischaemic heart disease. Recently, the
Myocardial Ischaemia Reduction with Aggressive
Cholesterol Lowering (MIRACL) study reported a
50% reduction in stroke with atorvastatin com-
pared with placebo.[13] There were 24 strokes with
placebo and 12 strokes with atorvastatin during the
16-week follow-up in this trial. The clinical benefit
seen in secondary prevention trials is corroborated
by 2 meta-analyses which demonstrate that statin
therapy lowers stroke risk by approximately 30%.[4,5]
Although the absolute stroke rate in these clin-
ical trials was small, the results did suggest that
statin therapy decreases ischaemic stroke without
increasing haemorrhagic stroke. In addition, statins
may reduce the effect of stroke by reducing stroke
size and through neuroprotective effects within the
cerebral vasculature and brain parenchyma.
carotid artery. This stabilisation occurs through the
lowering of lipid levels and cholesterol-indepen-
dent anti-inflammatory and antithrombotic actions
which operate within the plaque and the blood-
stream.[14-16] Reduced plaque disruption and throm-
bosis translates into reduced artery-to-artery throm-
boembolism.
4. Neuroprotective Properties of Statins
In addition to effects in the precerebral macro-
vasculature, emerging evidence indicates that
statins may ameliorate a number of pathophysio-
logical processes that occur within the cerebral
vasculature and brain parenchyma during cerebral
ischaemia and reperfusion. There are now experi-
mental data in animal models of stroke showing
that statins limit ischaemic damage by improving
blood flow to the ischaemic brain and by making
the brain parenchyma intrinsically more resistant
to the effects of ischaemia. It appears that modula-
tion of the cerebral endothelial nitric oxide (NO)
system by statin therapy is of primary importance
in providing such neuroprotection.
4.1 Nitric Oxide Synthase Isoforms and
Cerebral Ischaemia
3. Carotid and Aortic Plaque Instability
The different isoforms of nitric oxide synthase
(NOS) play important but opposing roles in cere-
bral ischaemia. The inducible form of NOS (iNOS)
is an important mediator of inflammatory re-
sponses during ischaemia and reperfusion.[17] As-
trocytes elaborate iNOS in response to a series of
proinflammatory cytokines such as interleukin (IL)-
1β, tumour necrosis factor-α (TNFα) and IL-6.[18]
NO, derived from iNOS in both astrocytes and
macrophages, and its oxidative by-product peroxy-
nitrite, are thought to contribute to neuronal death
due to oxidation of structural neuronal proteins
during ischaemia. Additionally, neuronal NO (pro-
duced by neuronal NOS; nNOS) may contribute to
neurological damage by promoting glutamate-
mediated neurotoxicity. On the other hand, NO
produced by endothelial NOS (eNOS) can have a
protective physiological role. This form of NO orches-
trates the paracrine homeostatic functions of the
The majority of nonlacunar ischaemic strokes
are caused by thromboemboli arising from athero-
matous plaques in the carotid artery or the aorta.
Hypercholesterolaemia is an important risk factor
for the development of atherosclerosis. The Asymp-
tomatic Carotid Artery Progression Study (ACAPS)[7]
demonstrated reversal or slowing of the typical
progression of intimal-medial thickening in the
carotid artery (using B-mode ultrasound) in men
and women with moderately elevated cholesterol
levels who received lovastatin for 3 years. Simi-
larly, the Pravastatin, Lipids, and Atherosclerosis
in the Carotids II (PLACII) study[8] demonstrated
a significant 35% reduction in carotid intimal-
medial thickness with pravastatin (also using B-
mode ultrasound). Several lines of evidence sug-
gest that statins would reduce stroke by stabilising
atheromatous plaque in the proximal aorta and
© Adis International Limited. All rights reserved.
CNS Drugs 2001; 15 (8)

592
Vaughan et al.
endothelium, which include inhibition of leucocyte
and platelet adhesion, control of vascular tone, and
maintenance of a thromboresistant interface be-
tween the bloodstream andthevessel wall. Micelack-
ing the gene for eNOS experienced larger infarcts
after middle cerebral artery occlusion,[19] whereas
iNOS null mice had significantly reduced infarct
volumes[20] compared with wild-type controls. To-
gether, these observations suggest a relative com-
partmentalisation of NOS isoform activity in the
brain, with contrasting roles for eNOS and iNOS
in the setting of ischaemia. Preliminary studies
with statins have demonstrated that these com-
pounds may be able to modulate brain NOS iso-
form activity in a neuroprotective manner.
tion of eNOS. It has been shown in mice that dis-
ruption of endothelial cell actin cytoskeleton with
Rho inhibitors such as Clostridium botulinum C3
transferase, cytochalasin D and simvastatin in-
creases eNOS activity and expression, increases
cerebral blood flow and reduces infarct size.[25]
The mechanism by which the actin cytoskeleton
modulates eNOS appears primarily to be its action
on the post-translational stability of eNOS mRNA.
In this regard, other compounds that affect this
pathway may also hold promise as neuroprotective
agents.
Additional important effects of statins on the
bioavailability of NO may be mediated by alter-
ations in the activity of the protein kinase Akt.[26]
Akt plays a central role in orchestrating a spectrum
of cellular events, including activation of eNOS
and promotion of endothelial cell survival.[27]
Simvastatin therapy potentiates the activity of Akt,
which in turn may stimulate eNOS and lead to an
increased production of NO (fig. 2).[26]
4.1.1 Statin Therapy Potentiates Endothelial Nitric
Oxide Synthase
Statin therapy improves abnormal endothelial
control of vasomotor function in both the coronary
and forearm circulations in dyslipidaemic individ-
uals.[21,22] Similarly, statin therapy may be benefi-
cial during cerebral ischaemia through the modu-
lation of brain eNOS. Experimental data from a
murine model of ischaemic stroke demonstrate that
prophylactic statin therapy augments cerebral
blood flow, reduces infarct size by approximately
30%, and improves neurological outcomes in normo-
cholesterolaemic animals.[23] In this model, statin
therapy directly up-regulated eNOS activity in the
brain, without altering expression of nNOS. These
effects occurred independent of change in choles-
terol level and were reversible with mevalonate or
geranyl-geranyl pyrophosphate co-treatment. In a
similar study, atorvastatin has been shown to re-
duce stroke size in normocholesterolaemic mice
through cholesterol-independent mechanisms.[24]
This effect is mediated by up-regulation of eNOS
in the vasculature and platelets and by decreased
platelet activation.
The effects of statins on the endothelial cell
eNOS-NO pathway may be pivotal in protecting
the brain during states of compromised blood flow.
Potentiation of NO may improve collateral blood
flow to ischaemic areas, enhance cerebral arterial
vasodilator responses, prevent apoptosis and pos-
sibly promote angiogenesis.
4.2 Antineuroinflammatory Actions
of Statins
As well as biochemically remodelling the en-
dothelium, HMG-CoA reductase inhibitors have
been shown to inhibit a number of inflammatory
processes active during cerebral ischaemia and re-
perfusion.
4.2.1 Statins and Adhesion Molecule Regulation
Up-regulation of adhesion molecule expression
has been documented in animal and human cere-
bral ischaemia and reperfusion.[28] Enhanced ex-
pression of adhesion molecules on both endothe-
lium and glial cells within the infarct and in the
surrounding ischaemic penumbra may facilitate
postischaemic migration of leucocytes through the
brain parenchyma. Statin therapy inhibits leucocyte-
The small guanine triphosphate (GTP)–binding
protein Rho both downregulates eNOS, and re-
duces eNOS mRNA stability via effects on the en-
dothelial cell actin cytoskeleton (fig. 2). HMG-
CoA reductase inhibitors reduce the isoprenylation
(and the activity) of Rho, allowing the up-regula-
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CNS Drugs 2001; 15 (8)

Statins in Cerebral Ischaemia and Stroke
593
NO
PDK-1
Akt
Acetyl-CoA
PIP2
Anti-inflammatory
Vasodilatory
Antithrombotic
Angiogenic
PIP3
+
eNOS
NO
HMG-CoA
−
HMG-CoA R I
−
+
Mevalonate
PI3K
Rho
−
eNOS mRNA
Rho
+
Actin
GGP
cytoskeleton
eNOS
Fig. 2. Molecular actions of statins on the endothelial nitric oxide system. Endothelial nitric oxide synthase (eNOS) mediates the
anti-inflammatory and vasodilatory functions of the cerebral endothelium. Mevalonate, the product of β-hydroxy-β-methylglutaryl
coenzymeA(HMG-CoA)reductase, inhibitsphosphatidylinositol3-kinase(PI3K). PI3Kconverts phosphatidylinositol 4,5 biphosphate
(PIP2) to phosphatidylinositol 3,4,5 triphosphate (PIP3) which in turn activates protein kinase Akt via phosphoinositide-dependent
kinase-1 (PDK-1). Acetyl-CoA = acetyl coenzyme A; GGP = geranyl-geranyl pyrophosphate; HMG-CoA R I = HMG-CoA reductase
inhibitor; mRNA = messenger RNA; NO = nitric oxide; Rho = guanine triphosphate–binding protein.
endothelial interactions in hypercholesterolaemic
animals[29] and neutrophil adhesion to coronary
endothelium.[30] In humans with hypercholesterol-
aemia, simvastatin and lovastatin both reduce mono-
cyte CD11b expression as well as ex vivo CD11b-
dependent monocyte adhesion to endothelium.[31]
This effect may be mediated through reduced iso-
prenylation of leucocyte G-proteins,[32] reduced
isoprenoid-dependent anchoring or reduced dimeri-
sation of adhesion molecules such as CD11b/CD18
on monocytes.
and the cerebral endothelium, promote cell migra-
tion, enhance thrombogenesis through tissue factor
expression, and augment elaboration of platelet-
activating factor.[33] IL-1β, a proinflammatory cyto-
kine, is overexpressed in the brains of experimental
animals after stroke and appears to contribute to
neuronal damage, perhaps through induction of
neuronal apoptosis.[34] Other inflammatory cyto-
kines, such as TNFα and IL-6, are also elevated in
experimental models of cerebral ischaemia and may
contribute to further neuronal loss.[28] TNFα not
only up-regulates adhesion molecule expression
by glial and endothelial cells, but also alters the
blood-brain barrier and mediates a prothrombotic
transformation of the cerebral endothelium.[28]
The clinical relevance of such inflammatory
mediators is suggested by experimental studies
demonstrating a reduction in cerebral infarct size
in animals treated with cytokine receptor antag-
onists.[35] Lovastatin has been shown to inhibit
4.2.2 Statins and Cytokine Activity
Statin therapy may also modulate CNS cytokine
production. Cytokines are prominent mediators of
inflammatory and immunological responses in the
brain and are produced by neurons, glial cells and
endothelium. Although the precise role of different
cytokines in cerebral ischaemic syndromes remains
to be elucidated, cytokines appear to modulate ad-
hesion molecule expression on inflammatory cells
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CNS Drugs 2001; 15 (8)

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Vaughan et al.
cytokine-mediated up-regulation of iNOS and pro-
duction of NO in rat astrocytes and macrophages.[36]
Thus, statin therapy may represent a novel means
of suppressing cytokine responses occurring during
ischaemia and reperfusion, by directly reducing the
in vivo induction of inflammatory mediators such
as iNOS, IL-1β and TNFα in astrocytes and macro-
phages.[36] When these effects are coupled with the
observed effects of statins on eNOS (section 4.1),
it appears that they may provide neuroprotection
by simultaneously up-regulating eNOS and in-
hibiting iNOS in the ischaemic brain. Since many
of these effects of statins are reversible with co-
administration of mevalonate or farnesyl pyro-
phosphate (section 4.1), statins may reduce inflam-
mation by decreasing the isoprenylation (and hence
the activity) of proteins involved in intracellular
signalling and inflammation.[36]
Recent data indicate that statins also directly
effect immune cell activation. Therapy with statins
inhibits interferon-γ–induced expression of class
II major histocompatibility complex on antigen-
presenting cells and reduces T cell activation.[37]
Therefore, some of the antiatherosclerotic and anti-
inflammatory actions of statins may be due to modu-
lation of the immune system.
protective endogenous antioxidant systems (such
as the enzymes superoxide dismutase and catalase)
may be overwhelmed.
Several studies indicate that therapy with statins
can reduce lipoprotein oxidation and ameliorate
free radical injury. Statins may have broader anti-
oxidant effects than those measured by several ex
vivo systems, such as increased lag time of copper-
induced LDL oxidation[41] and reduced leucocyte-
induced LDL oxidation.[42] Hydroxy metabolites of
atorvastatin have been shown in an in vitro model
to inhibit oxidation in a concentration-dependent
manner.[43] In a study in patients with hyperchol-
esterolaemia, treatment with simvastatin increased
the α-tocopherol : total cholesterol ratio,[44] thereby
possibly enhancing membrane-specific antioxidant
defences. Most studies have explored the antioxi-
dant properties of statins in relation to LDL, but
statins may exert broader antioxidant effects by
preserving superoxide dismutase activity.[42]
5. Future Directions
Although it has been demonstrated that statin
therapy reduces stroke in secondary prevention
trials in patients with coronary artery disease
(section 2), a number of important issues are yet to
be addressed. Roles for statin therapy in the pri-
mary prevention of stroke and in the prevention of
small vessel and multi-infarct neurological disease
remain unknown. Statin therapy may reduce the
incidence of dementia;[45,46] but this has not yet
been demonstrated in a prospective clinical trial.
However, large prospective clinical trials designed
to address some of these issues are underway. For
instance, the Prospective Study of Pravastatin in
the Elderly at Risk (PROSPER) will examine the
effect of statin therapy on major combined end-
points (death, myocardial infarction and stroke)
and cognitive decline in patients aged 70 to 82
years.[47] Further investigation using a number of
modalities, including neuroimaging studies and
cognitive studies, are warranted to explore putative
neuroprotective properties of statins. If the po-
tential cholesterol-independent neuroprotective
effects of statins are proved to be clinically im-
4.3. Antioxidant Effects of Statins
Finally, statins may provide neuroprotection
through antioxidant effects. Oxidative injury ap-
pears to be a fundamental mechanism of many
neurological disorders including cerebrovascular
disease.[38,39] Chronic oxidant injury plays a patho-
physiological role in precerebral atherogenesis and
free radical generation following stroke. Thus,
oxidant injury, during both spontaneous and thera-
peutic reperfusion, may accentuate tissue injury in
the ischaemic penumbra. The generation of free
radicals causes neuronal and endothelial damage
through the induction of lipid peroxidation, protein
oxidation and direct damage to nucleic acids. The
elaboration of reactive oxygen species has been re-
ported to induce apoptosis of endothelial cells
through activation of CPP32-like proteases.[40]
Moreover, during ischaemia and reperfusion, the
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CNS Drugs 2001; 15 (8)

Statins in Cerebral Ischaemia and Stroke
595
14. Delanty N, Vaughan CJ. Vascular effects of statins in stroke.
Stroke 1997; 28: 2315-20
15. Vaughan CJ, Murphy MB, Buckley BM. Statins do more than
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16. Vaughan CJ, Gotto Jr AM, Basson CT. The evolving role of
statins in the management of atherosclerosis. J Am Coll Cardiol
2000; 35: 1-10
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wide-ranging utility in the management of a vari-
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17. Samdani AF, Dawson TM, Dawson VL. Nitric oxide synthase
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Acknowledgements
The authors are grateful for support from a New York
Academy of Medicine Glorney-Raisbeck Fellowship (CJV),
NIH-HL03468 (CTB), and the Michael Wolk Cardiovascu-
lar Foundation (CTB).
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Correspondence and offprints: Dr Craig T. Basson, Cardiol-
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E-mail: ctbasson@mail.med.cornell.edu
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