(Stroke. 1999;30:1969-1973.)
© 1999 American Heart Association, Inc.
Comments, Opinions, and Reviews |
Neuroprotective Properties of Statins in Cerebral Ischemia and Stroke
From the Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, The New York Presbyterian Hospital, New York, NY (C.J.V.), and Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, Pa (N.D.).
Correspondence to Carl J. Vaughan, MD, Cardiology Division, Department of Medicine, Weill Medical College of Cornell University, The New York Presbyterian Hospital, Starr 4, 525 E 68th St, New York, NY 10021. E-mail cvaughan{at}nyhs.med.cornell.edu
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Abstract |
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 Top Abstract IntroductionDownstream EffectsUpstream EffectsEndotheliumInflammationAntioxidant EffectsFuture DirectionsReferences |
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Background—The atheroma-retarding properties of ß-hydroxy-ß-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, or "statins," in both the coronary and carotid arterial beds are well established. However, a growing body of recent data suggests that statins possess important adjunctive properties that may confer additional benefit beyond the retardation of atherosclerosis. In this article, we review the emerging evidence that statins have beneficial effects within the cerebral circulation and brain parenchyma during ischemic stroke and reperfusion.
Summary of Review—Clinical studies show that statins reduce the incidence of ischemic stroke through probable effects on precerebral atherosclerotic plaque and through antithrombotic mechanisms. Additionally, statins have been shown to reduce infarct size in experimental animal models of stroke. Statins both upregulate endothelial nitric oxide synthase (eNOS) and inhibit inducible nitric oxide synthase (iNOS), effects that are potentially neuroprotective. The preservation of eNOS activity in cerebral vasculature, particularly in the ischemic penumbra, may be especially important in preserving blood flow and limiting neurological loss. Statins may also attenuate the inflammatory cytokine responses that accompany cerebral ischemia, and they possess antioxidant properties that likely ameliorate ischemic oxidative stress in the brain.
Conclusions—In addition to reducing stroke, the statin class of drugs exhibits a number of important neuroprotective properties that likely attenuate the effects of ischemia on the brain vasculature and parenchyma. Further investigation of the role of statins in human neuroprotection by use of neuroimaging and cognitive studies is warranted to explore these preliminary observations. In addition to reducing ischemic stroke, early evidence indicates that statins may also be neuroprotective.
Key Words: endothelium • HMG-CoA reductase inhibitors • inflammation • nitric oxide • neuroprotection
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Introduction |
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TopAbstractIntroductionDownstream EffectsUpstream EffectsEndotheliumInflammationAntioxidant EffectsFuture DirectionsReferences |
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Recent clinical trials and meta-analyses of ß-hydroxy-ß-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke in patients with a history of coronary artery disease, both with and without elevations of serum cholesterol. Statins have been shown to attenuate the development of atherosclerosis in both the coronary and carotid arterial beds ("downstream effects"). Recent data suggest that statins have other beneficial properties in addition to the retardation of atherosclerosis. In this article, we review the emerging evidence that statins have additional beneficial "upstream effects" in cerebrovascular disease. We review anti-inflammatory, antioxidant, and endothelial protective effects of statins and discuss the putative neuroprotective properties of these compounds in cerebral ischemic syndromes.
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Downstream Effects |
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TopAbstractIntroductionDownstream EffectsUpstream EffectsEndotheliumInflammationAntioxidant EffectsFuture DirectionsReferences |
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Despite the established role of cholesterol in the pathogenesis of coronary artery disease, current epidemiological evidence does not demonstrate a clear relationship between the risk of stroke and serum cholesterol level.1 2 However, recent studies indicate that statins significantly reduce ischemic stroke. In the CARE study,3 pravastatin significantly reduced the specified end point of stroke by 31%, without increased hemorrhagic stroke. Post hoc analysis of the 4S trial4 showed a similar significant reduction in stroke. This clinical benefit seen in secondary prevention trials is corroborated by 2 meta-analyses5 6 that demonstrate that statin therapy lowers stroke risk by
30%. The clinical benefit of statins
is also supported by the observation that statin treatment reduces
progression of carotid intima-media thickening.7 The
majority of nonlacunar ischemic strokes are caused by
thromboemboli arising from atheromatous disease outside
the brain, such as the carotid artery or the aortic arch, vascular
sites in which hypercholesterolemia is an
important risk factor for the development of
atherosclerosis. The downstream benefit of statins is
therefore likely due to the stabilization of
atherosclerosis at these sites, in addition to
favorable hemorheological and antithrombotic properties of statins,
which decrease plaque disruption and reduce artery-to-artery
thromboembolism.8 9 |
Upstream Effects |
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TopAbstractIntroductionDownstream EffectsUpstream EffectsEndotheliumInflammationAntioxidant EffectsFuture DirectionsReferences |
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In addition to the above effects in the precerebral macrovasculature, emerging evidence indicates that statins may have important upstream effects that ameliorate a number of pathophysiological processes that occur within the cerebral vasculature and brain parenchyma during cerebral ischemia and reperfusion. The data suggest that statins can ameliorate ischemic damage by improving blood flow to the ischemic brain and by making the brain parenchyma intrinsically more resistant to the effects of ischemia. The clinical importance of protecting cerebral microvascular integrity is highlighted by recent observations indicating that silent strokes are much more prevalent than previously suspected. This has been elegantly demonstrated with MRI in the Cardiovascular Health Study,10 in which the incidence of infarct-like lesions (ILLs) in subjects aged >65 years was 31%. In this study, the presence of ILLs correlated with both cognitive decline and motor deficit. Although the impact of statins on ILLs has not been studied to date, it is possible that statin therapy may become an important means of reducing silent stroke and preventing vascular neurological decline. This effect may be accentuated by concomitant antiplatelet therapy, although this has not been investigated with prospective neuroimaging studies.
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Endothelium |
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TopAbstractIntroductionDownstream EffectsUpstream EffectsEndotheliumInflammationAntioxidant EffectsFuture DirectionsReferences |
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The different isoforms of nitric oxide synthase (NOS) play important but opposing roles in cerebral ischemia. The inducible form of NOS (iNOS) has been implicated as an important mediator of inflammatory responses during ischemia and reperfusion.11 Astrocytes elaborate iNOS in response to a series of proinflammatory mediators, including cytokines such as interleukin-1ß (IL-1ß), tumor necrosis factor-
(TNF-), and
interleukin-6 (IL-6).12 Expression of iNOS has been
demonstrated in neutrophils infiltrating the ischemic brain and
in blood vessels within the ischemic territory in human
ischemic stroke.13 Nitric oxide (NO) derived from
iNOS in both astrocytes and macrophages and its oxidative
by-product peroxynitrite are thought to contribute to neuronal
death due to oxidation of structural neuronal proteins during
ischemia (Figure 1
).
Additionally, neuronal NO (produced by neuronal NOS) may contribute to
neurological damage by promoting glutamate-mediated neurotoxicity. In
contrast, NO produced by endothelial NOS (eNOS) has a
protective physiological role and orchestrates the
paracrine homeostatic functions of the endothelium,
which include inhibition of leukocyte and platelet adhesion,
control of vascular tone, and maintenance of a
thromboresistant interface between the bloodstream and the
vessel wall (Figure 1). Consistent with the concept that
eNOS plays a protective role in focal cerebral ischemia is the
observation that eNOS knockout animals experience larger infarcts after
middle cerebral artery occlusion.14 In contrast, mice
lacking the gene for iNOS have significantly reduced infarct volumes
compared with wild-type controls.15 Together, these
fascinating observations suggest a relative compartmentalization of NOS
isoform activity in the brain, with contrasting roles for eNOS and iNOS
in the setting of ischemia. Preliminary studies with statins
have demonstrated that these compounds may be able to modulate brain
NOS isoform activity in a neuroprotective manner.
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Statin therapy favorably modifies endothelial control
of vasomotor function in both the coronary and forearm
circulations.16 17 Similarly, statin therapy may be
beneficial during cerebral ischemia through the modulation of
brain eNOS. Recent experimental data from a murine model of
ischemic stroke demonstrate that prophylactic
statin therapy augments cerebral blood flow, reduces infarct size by
30%, and improves neurological outcome in
normocholesterolemic animals.18 In this
intriguing investigation, statin therapy directly upregulated eNOS
activity in the brain without altering expression of nNOS. These
effects occurred independently of change in cholesterol
level and were reversible by cotreatment with mevalonate or
geranylgeranyl pyrophosphate. This suggests that intermediates in
cholesterol biosynthesis independently modulate eNOS.
Although untested in humans, this observation suggests that statins may
protect the cerebral endothelium and attenuate
ischemic burden.
Astrocytes exhibit both constitutive NOS and iNOS activity under various conditions, and activated microglia also express iNOS.19 The induction of iNOS in glial cells may occur in response to ischemia or proinflammatory signals. Excessive glial cell–derived production of NO can be toxic to neurons in the surrounding brain, thus contributing to further neuronal loss. Recent observations suggest that statin therapy modulates the activity of iNOS. Lovastatin has been shown to inhibit cytokine-mediated upregulation of iNOS and production of NO in rat astrocytes and macrophages.20 Given the putative deleterious effects of this NOS isoform in the central nervous system, its inhibition by statins may suppress inflammatory responses that accompany acute ischemia. Moreover, in aggregate, these observations suggest a dual role for statins in cerebral ischemia, whereby they may simultaneously upregulate eNOS and inhibit iNOS in a synergistically neuroprotective manner.
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Inflammation |
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In addition to biochemically remodeling the endothelium, HMG-CoA reductase inhibitors have been shown to inhibit a number of inflammatory processes known to be important during cerebral ischemia and reperfusion. Upregulation of adhesion molecule expression has been documented in animal and human cerebral ischemia and reperfusion.21 It has been postulated that the enhanced expression of adhesion molecules on both endothelium and glial cells within the infarct and in the surrounding ischemic penumbra facilitates postischemic migration of leukocytes through the brain parenchyma. Statin therapy has been shown to reduce enhanced leukocyte-endothelium interactions in hypercholesterolemic animals22 and to inhibit neutrophil adhesion to coronary endothelium.23 In humans, both simvastatin and lovastatin reduce monocyte CD11b expression and ex vivo CD11b-dependent monocyte adhesion to endothelium in subjects with hypercholesterolemia.24 It has been speculated that this effect may be mediated through reduced isoprenylation of leukocyte G-proteins25 or reduced isoprenoid-dependent anchoring or dimerization of adhesion molecules such as CD11b/CD18 on monocytes (Figure 2
). Because statin therapy has been shown
to reduce monocyte adhesion molecule expression, and anti-CD11b/CD18
monoclonal antibodies have been shown to reduce ischemic cell
damage after transient middle cerebral artery occlusion,26
statin therapy may also reduce neurological injury through effects on
adhesion molecule expression or behavior.
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In addition to these potential salutary effects on adhesion molecules,
statin therapy may modulate central nervous system cytokine
production. Cytokines are prominent mediators of
inflammatory and immunologic responses in the brain and are produced by
neurons, glial cells, and endothelium (Figure 1
). Although the precise role of different cytokines in
cerebral ischemic syndromes remains to be elucidated,
cytokines appear to modulate adhesion molecule expression on
cerebral endothelium and inflammatory cells, promote
cell migration, enhance thrombogenesis through tissue factor
expression, and augment elaboration of platelet activating
factor.27 IL-1ß, a proinflammatory cytokine, is
overexpressed in the brains of experimental animals after stroke and
appears to contribute to neuronal damage, perhaps through induction of
neuronal apoptosis.28 Although it has been
suggested that TNF- is neuroprotective,29 30 TNF-
and IL-6 are elevated in experimental models of cerebral
ischemia and may contribute to neuronal loss.21
TNF- not only upregulates adhesion molecule expression by glial and
endothelial cells but also alters the blood-brain
barrier and mediates a prothrombotic transformation of the cerebral
endothelium.21 Although the precise role
of different cytokines in cerebral ischemia needs
further clarification, the importance of cytokines in
ischemia is highlighted by experimental studies demonstrating a
reduction in cerebral infarct size in animals treated with
cytokine receptor antagonists.31 Thus,
statin therapy may represent a novel means of suppressing
cytokine responses that occur during ischemia and
reperfusion by directly reducing the in vivo induction of inflammatory
mediators such as iNOS, IL-1ß, and TNF- in astrocytes and
macrophages. The demonstration that these effects of statins
are reversible with coadministration of mevalonate or farnesyl
pyrophosphate suggests that statins may be anti-inflammatory because
they decrease isoprenylation (and hence activity) of proteins involved
in intracellular signaling and inflammation20 (Figure 2). In summary, these preliminary observations support the
concept that statins represent a novel means of attenuating
inflammatory neuronal loss occurring during cerebral
ischemia.
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Antioxidant Effects |
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TopAbstractIntroductionDownstream EffectsUpstream EffectsEndotheliumInflammationAntioxidant EffectsFuture DirectionsReferences |
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Finally, HMG-CoA reductase inhibitors may be neuroprotective through potential antioxidant effects. Oxidative injury appears to be a fundamental mechanism of many neurological disorders, including cerebrovascular disease.32 33 Chronic oxidant injury may play a pathophysiological role in precerebral atherogenesis, and the enhanced liberation of free radical species after acute stroke and during both spontaneous and therapeutic reperfusion may accentuate tissue injury in the ischemic 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 (Figure 1
). The elaboration of reactive oxygen species has been
reported to induce apoptosis of endothelial
cells through activation of CPP32-like proteases.34
Moreover, during ischemia and reperfusion, the protective
endogenous antioxidant systems (such as the enzymes
superoxide dismutase and catalase) may be overwhelmed.
Several studies indicate that therapy with statins may reduce
lipoprotein oxidation and ameliorate free radical injury. As well as
having favorable antioxidant effects as measured by several ex vivo
systems, such as increased lag time of copper-induced LDL
oxidation35 and reduced leukocyte-induced LDL
oxidation,36 statins may have broader antioxidant effects.
Hydroxy metabolites of atorvastatin have been shown in an in vitro
model to inhibit oxidation in a concentration-dependent
manner,37 and in a study of
hypercholesterolemic patients, treatment with
simvastatin increased the -tocopherol/total
cholesterol ratio,38 thus possibly boosting
membrane-specific antioxidant defenses. Most studies have explored the
antioxidant properties of statins in relation to LDL; however, statins
may exert broader antioxidant effects through preservation of
superoxide dismutase activity.36
In addition to antioxidant properties, it has been shown that statins may reduce the biosynthesis of the endogenous lipophilic mitochondrial antioxidant coenzyme Q10, or ubiquinone.39 Although this effect could negate any potential free radical–scavenging actions of statins, the combined exogenous administration of a statin with coenzyme Q10 could exert potent synergistic neuroprotective and antioxidant effects, because coenzyme Q10 itself appears to have important neuroprotective effects.40 To the best of our knowledge, this approach has yet to be tested either in animal models or in humans.
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Future Directions |
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TopAbstractIntroductionDownstream EffectsUpstream EffectsEndotheliumInflammationAntioxidant EffectsFuture DirectionsReferences |
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In addition to reducing ischemic stroke, there is an emerging body of evidence indicating that statins are also neuroprotective. Statins reduce the incidence of ischemic stroke through downstream effects by pacifying precerebral atherosclerotic plaque and through their antithrombotic actions. Statins have a number of additional upstream effects within the cerebral vasculature and brain parenchyma that are potentially neuroprotective in the setting of cerebral ischemia and reperfusion. These emerging neuroprotective properties of statins may confer significant additional clinical benefit (Figure 3
). There is also growing evidence
indicating that some of these effects are cholesterol
independent and are mediated by interruption of isoprenoid
biosynthesis. Therapy with HMG-CoA reductase inhibitors may
remodel endothelium in a manner that may become
clinically important in the face of a proximate ischemic
insult. In particular, the preservation of eNOS activity in cerebral
vasculature, and especially in the ischemic penumbra, may limit
neurological deficit. Moreover, putative anti-inflammatory and
antioxidant properties of statins may confer additional
neuroprotection.
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Given the already widespread indications for statin usage, it is interesting to speculate that these drugs possess additional important neuroprotective properties within the central nervous system. Further investigation with a number of modalities, including neuroimaging studies and cognitive studies, are warranted to explore these preliminary observations. If these potential cholesterol-independent neuroprotective effects of statins are proven to be clinically important in human neuroprotection, this class of drugs will find wide-ranging utility in the management of a variety of cerebrovascular disease entities in patients with and without hypercholesterolemia.
Received May 28, 1999; revision received June 17, 1999; accepted June 17, 1999.
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 M. Cimino, P. Gelosa, A. Gianella, E. Nobili, E. Tremoli, and L. Sironi Statins: Multiple Mechanisms of Action in the Ischemic Brain Neuroscientist, June 1, 2007; 13(3): 208 - 213. [Abstract] [PDF]
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 S. C. Fagan, H. F. Elewa, and D. J. Rychly Statin Therapy for Secondary Stroke Prevention: Evidence Catches Up to Practice Journal of Pharmacy Practice, April 1, 2007; 20(2): 117 - 122. [Abstract] [PDF]
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J. Alvarez-Sabin, R. Huertas, M. Quintana, M. Rubiera, P. Delgado, M. Ribo, C. A. Molina, and J. Montaner Prior Statin Use May Be Associated With Improved Stroke Outcome After Tissue Plasminogen Activator Stroke, March 1, 2007; 38(3): 1076 - 1078. [Abstract] [Full Text] [PDF]
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 D. D. Waters, J. C. LaRosa, P. Barter, J.-C. Fruchart, A. M. Gotto Jr, R. Carter, A. Breazna, J. J.P. Kastelein, and S. M. Grundy Effects of High-Dose Atorvastatin on Cerebrovascular Events in Patients With Stable Coronary Disease in the TNT (Treating to New Targets) Study J. Am. Coll. Cardiol., November 7, 2006; 48(9): 1793 - 1799. [Abstract] [Full Text] [PDF]
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 D. Deplanque, I. Masse, C. Lefebvre, C. Libersa, D. Leys, and R. Bordet Prior TIA, lipid-lowering drug use, and physical activity decrease ischemic stroke severity Neurology, October 24, 2006; 67(8): 1403 - 1410. [Abstract] [Full Text] [PDF]
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H. J. Zambarakji, T. Nakazawa, E. Connolly, A. M. Lane, S. Mallemadugula, M. Kaplan, N. Michaud, A. Hafezi-Moghadam, E. S. Gragoudas, and J. W. Miller Dose-dependent effect of pitavastatin on VEGF and angiogenesis in a mouse model of choroidal neovascularization. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2623 - 2631. [Abstract] [Full Text] [PDF]
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J. Kennedy, H. Quan, A. M. Buchan, W. A. Ghali, and T. E. Feasby Statins Are Associated With Better Outcomes After Carotid Endarterectomy in Symptomatic Patients Stroke, October 1, 2005; 36(10): 2072 - 2076. [Abstract] [Full Text] [PDF]
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H. D. Aronow, M. Shishehbor, D. A. Davis, I. L. Katzan, D. L. Bhatt, C. T. Bajzer, A. Abou-Chebl, K. W. Derk, P. L. Whitlow, and J. S. Yadav Leukocyte Count Predicts Microembolic Doppler Signals During Carotid Stenting: A Link Between Inflammation and Embolization Stroke, September 1, 2005; 36(9): 1910 - 1914. [Abstract] [Full Text] [PDF]
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M.-Y. Tseng, M. Czosnyka, H. Richards, J. D. Pickard, and P. J. Kirkpatrick Effects of Acute Treatment With Pravastatin on Cerebral Vasospasm, Autoregulation, and Delayed Ischemic Deficits After Aneurysmal Subarachnoid Hemorrhage: A Phase II Randomized Placebo-Controlled Trial Stroke, August 1, 2005; 36(8): 1627 - 1632. [Abstract] [Full Text] [PDF]
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M. S.V. Elkind, A. C. Flint, R. R. Sciacca, and R. L. Sacco Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality Neurology, July 26, 2005; 65(2): 253 - 258. [Abstract] [Full Text] [PDF]
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S. Nagotani, T. Hayashi, K. Sato, W. Zhang, K. Deguchi, I. Nagano, M. Shoji, and K. Abe Reduction of Cerebral Infarction in Stroke-Prone Spontaneously Hypertensive Rats by Statins Associated With Amelioration of Oxidative Stress Stroke, March 1, 2005; 36(3): 670 - 672. [Abstract] [Full Text] [PDF]
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G. Li, R. Higdon, W. A. Kukull, E. Peskind, K. Van Valen Moore, D. Tsuang, G. van Belle, W. McCormick, J. D. Bowen, L. Teri, et al. Statin therapy and risk of dementia in the elderly: A community-based prospective cohort study Neurology, November 9, 2004; 63(9): 1624 - 1628. [Abstract] [Full Text] [PDF]
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M. Endres and U. Laufs Effects of Statins on Endothelium and Signaling Mechanisms Stroke, November 1, 2004; 35(11_suppl_1): 2708 - 2711. [Abstract] [Full Text] [PDF]
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H. L. Lazar Role of statin therapy in the coronary bypass patient Ann. Thorac. Surg., August 1, 2004; 78(2): 730 - 740. [Abstract] [Full Text] [PDF]
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 K.M.A. Welch Statins for the prevention of cerebrovascular disease: the rationale for robust intervention Eur. Heart J. Suppl., July 1, 2004; 6(suppl_C): C34 - C42. [Abstract] [Full Text] [PDF]
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K.-H. Jung, K. Chu, S.-W. Jeong, S.-Y. Han, S.-T. Lee, J.-Y. Kim, M. Kim, and J.-K. Roh HMG-CoA Reductase Inhibitor, Atorvastatin, Promotes Sensorimotor Recovery, Suppressing Acute Inflammatory Reaction After Experimental Intracerebral Hemorrhage Stroke, July 1, 2004; 35(7): 1744 - 1749. [Abstract] [Full Text] [PDF]
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J. Marti-Fabregas, M. Gomis, A. Arboix, A. Aleu, J. Pagonabarraga, R. Belvis, D. Cocho, J. Roquer, A. Rodriguez, M. D. Garcia, et al. Favorable Outcome of Ischemic Stroke in Patients Pretreated with Statins Stroke, May 1, 2004; 35(5): 1117 - 1121. [Abstract] [Full Text] [PDF]
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 G. H. Danton and W. D. Dietrich The Search for Neuroprotective Strategies in Stroke AJNR Am. J. Neuroradiol., February 1, 2004; 25(2): 181 - 194. [Full Text] [PDF]
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 V W Henderson, J R Guthrie, and L Dennerstein Serum lipids and memory in a population based cohort of middle age women J. Neurol. Neurosurg. Psychiatry, November 1, 2003; 74(11): 1530 - 1535. [Abstract] [Full Text] [PDF]
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W. Balduini, E. Mazzoni, S. Carloni, M. G. De Simoni, C. Perego, L. Sironi, and M. Cimino Prophylactic but Not Delayed Administration of Simvastatin Protects Against Long-Lasting Cognitive and Morphological Consequences of Neonatal Hypoxic-Ischemic Brain Injury, Reduces Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} mRNA Induction, and Does Not Affect Endothelial Nitric Oxide Synthase Expression Stroke, August 1, 2003; 34(8): 2007 - 2012. [Abstract] [Full Text] [PDF]
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 D. Deplanque, P. Gele, O. Petrault, I. Six, C. Furman, M. Bouly, S. Nion, B. Dupuis, D. Leys, J.-C. Fruchart, et al. Peroxisome Proliferator-Activated Receptor-{alpha} Activation as a Mechanism of Preventive Neuroprotection Induced by Chronic Fenofibrate Treatment J. Neurosci., July 16, 2003; 23(15): 6264 - 6271. [Abstract] [Full Text] [PDF]
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R. U. Pliquett, K. G. Cornish, J. D. Peuler, and I. H. Zucker Simvastatin Normalizes Autonomic Neural Control in Experimental Heart Failure Circulation, May 20, 2003; 107(19): 2493 - 2498. [Abstract] [Full Text] [PDF]
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 B. M Buckley Review: Lipids and stroke The British Journal of Diabetes & Vascular Disease, May 1, 2003; 3(3): 170 - 176. [Abstract] [PDF]
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 J.-C. Corvol, A. Bouzamondo, M. Sirol, J.-S. Hulot, P. Sanchez, and P. Lechat Differential Effects of Lipid-Lowering Therapies on Stroke Prevention: A Meta-analysis of Randomized Trials Arch Intern Med, March 24, 2003; 163(6): 669 - 676. [Abstract] [Full Text] [PDF]
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 L. Sironi, M. Cimino, U. Guerrini, A. M. Calvio, B. Lodetti, M. Asdente, W. Balduini, R. Paoletti, and E. Tremoli Treatment With Statins After Induction of Focal Ischemia in Rats Reduces the Extent of Brain Damage Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 322 - 327. [Abstract] [Full Text] [PDF]
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K. Gertz, U. Laufs, U. Lindauer, G. Nickenig, M. Bohm, U. Dirnagl, and M. Endres Withdrawal of Statin Treatment Abrogates Stroke Protection in Mice Stroke, February 1, 2003; 34(2): 551 - 557. [Abstract] [Full Text] [PDF]
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 P. Di Napoli, A.A. Taccardi, M. Oliver, and R. De Caterina Statins and stroke: evidence for cholesterol-independent effects Eur. Heart J., December 2, 2002; 23(24): 1908 - 1921. [PDF]
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 M. Honjo, H. Tanihara, K. Nishijima, J. Kiryu, Y. Honda, B. Y. J. T. Yue, and T. Sawamura Statin Inhibits Leukocyte-Endothelial Interaction and Prevents Neuronal Death Induced by Ischemia-Reperfusion Injury in the Rat Retina Arch Ophthalmol, December 1, 2002; 120(12): 1707 - 1713. [Abstract] [Full Text] [PDF]
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O. Neuhaus, S. Strasser-Fuchs, F. Fazekas, B.C. Kieseier, G. Niederwieser, H.P. Hartung, and J.J. Archelos Statins as immunomodulators: Comparison with interferon-{beta}1b in MS Neurology, October 8, 2002; 59(7): 990 - 997. [Abstract] [Full Text] [PDF]
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D. D. Waters, G. G. Schwartz, A. G. Olsson, A. Zeiher, M. F. Oliver, P. Ganz, M. Ezekowitz, B. R. Chaitman, S. J. Leslie, T. Stern, et al. Effects of Atorvastatin on Stroke in Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction: A Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Substudy Circulation, September 24, 2002; 106(13): 1690 - 1695. [Abstract] [Full Text] [PDF]
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 E. Gubina, T. Chen, L. Zhang, E. F. Lizzio, and S. Kozlowski CD43 polarization in unprimed T cells can be dissociated from raft coalescence by inhibition of HMG CoA reductase Blood, April 1, 2002; 99(7): 2518 - 2525. [Abstract] [Full Text] [PDF]
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P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]
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S. Wassmann, U. Laufs, K. Muller, C. Konkol, K. Ahlbory, A. T. Baumer, W. Linz, M. Bohm, and G. Nickenig Cellular Antioxidant Effects of Atorvastatin In Vitro and In Vivo Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 300 - 305. [Abstract] [Full Text] [PDF]
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F. Degraeve, M. Bolla, S. Blaie, C. Creminon, I. Quere, P. Boquet, S. Levy-Toledano, J. Bertoglio, and A. Habib Modulation of COX-2 Expression by Statins in Human Aortic Smooth Muscle Cells. INVOLVEMENT OF GERANYLGERANYLATED PROTEINS J. Biol. Chem., December 7, 2001; 276(50): 46849 - 46855. [Abstract] [Full Text] [PDF]
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M. Di Napoli and F. Papa Inflammation, Statins, and Outcome After Ischemic Stroke Stroke, October 1, 2001; 32 (10): 2446 - 2447. [Full Text] [PDF]
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W. Balduini, V. De Angelis, E. Mazzoni, and M. Cimino Simvastatin Protects Against Long-Lasting Behavioral and Morphological Consequences of Neonatal Hypoxic/Ischemic Brain Injury Stroke, September 1, 2001; 32(9): 2185 - 2191. [Abstract] [Full Text] [PDF]
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N. Jonsson and K. Asplund Does Pretreatment With Statins Improve Clinical Outcome After Stroke? : A Pilot Case-Referent Study Stroke, May 1, 2001; 32(5): 1112 - 1115. [Abstract] [Full Text] [PDF]
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L. B. Goldstein, R. Adams, K. Becker, C. D. Furberg, P. B. Gorelick, G. Hademenos, M. Hill, G. Howard, V. J. Howard, B. Jacobs, et al. Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association Circulation, January 2, 2001; 103(1): 163 - 182. [Full Text] [PDF]
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L. B. Goldstein, R. Adams, K. Becker, C. D. Furberg, P. B. Gorelick, G. Hademenos, M. Hill, G. Howard, V. J. Howard, B. Jacobs, et al. Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association Stroke, January 1, 2001; 32(1): 280 - 299. [Full Text] [PDF]
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U. Laufs, K. Gertz, P. Huang, G. Nickenig, M. Bohm, U. Dirnagl, M. Endres, and C. J. Vaughan Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thrombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice Editorial Comment Stroke, October 1, 2000; 31(10): 2442 - 2449. [Abstract] [Full Text] [PDF]
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D. Duval, C. J. Vaughan, and N. Delanty Effects of Statins on Ischemic Stroke: Neuroprotection and/or Triggering of Apoptotic Damage? • Response Stroke, April 1, 2000; 31 (4): 983 - 991. [Full Text]
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