Use of statins in CNS disorders
Introduction
The role of hypercholesterolemia in the pathogenesis of coronary heart disease (CHD) is clearly established, and there is convincing clinical evidence that lowering cholesterol, particularly with 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”), reduces coronary events [1], [2], [3], [4], [5], [6]. However, the role of cholesterol and cholesterol-lowering therapy in patients with cerebrovascular disease is controversial. While recent clinical trials and meta-analyses have shown that statins reduce stroke in patients with pre-existing CHD, the utility of statins for primary prevention of stroke in patients with isolated hypercholesterolemia, and for secondary prevention in stroke patients without CHD, is unproven.
Statins act primarily by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, resulting in an up-regulation of hepatic LDL receptor number with concomitant removal of total and LDL cholesterol from plasma. Statins also appear to have a variety of non-lipid mechanisms of action that may contribute to their clinical benefit. HMG-CoA reductase is responsible for the generation of isoprenoids, intermediates in the biosynthetic pathway of cholesterol that modifies the function and structure of a number of proteins [7]. Manipulation of this biosynthetic pathway with statins may have implications for treatment of other non-vascular disorders of the central nervous system (CNS).
Section snippets
Epidemiology
The relationship between cholesterol and stroke has been difficult to establish. Several epidemiological studies, including the Framingham Study and the Honolulu Heart Study, failed to show an association between blood cholesterol levels and stroke risk [8], [9], [10], [11]. This lack of association has been observed in the same population in which there was a strong correlation between cholesterol levels and CHD. The Prospective Studies Collaboration report, which observed 13,000 strokes among
Vascular mechanisms of stroke reduction
Angiographic studies have demonstrated that the degree of stenosis of pre-existing coronary lesions does not change dramatically with cholesterol-lowering therapy, despite significant decreases in event rates [26], [27], [28], [29]. This suggests that it is not only atheroma size and degree of luminal encroachment, but also the functional state of the plaque that determines the propensity for development of acute vascular occlusion [30]. Thrombosis typically develops on a plaque because either
Antiplatelet and antithrombotic effects
Platelets are an integral component in the pathogenesis of thromboembolism, and their function is altered in the setting of hypercholesterolemia. Patients with elevated LDL cholesterol have enhanced platelet aggregability, increased production of thromboxane A2 (the principal prostaglandin generated by platelets and a potent platelet activator), and elevated levels of markers of thrombin generation compared to normocholesterolemic individuals [50], [51], [52]. Statins appear to modify platelet
Possible neuroprotective effects
There is considerable evidence to suggest that statins, in addition to their role in prevention of vascular events as discussed above, have further mechanisms of action that may modify brain injury before, during, and after cerebral ischemia (Table 1).
Alzheimer's disease
Emerging evidence suggests a link between cholesterol and Alzheimer's disease (AD). While serum cholesterol levels of patients with AD have not been shown to differ from age-matched controls, there is some evidence that cholesterol levels may be elevated prior to development of the disease with a decline concurrent with disease progression [90], [91]. The presence of atherosclerosis, intimately related to elevated cholesterol levels, has been shown to correlate with an increased risk of AD.
Potential negative effects of statins
Despite the catalog of experimental data showing beneficial effects of the statins, several observations demand caution. Inhibition of cholesterol synthesis by statins has been shown to induce apoptosis in several models, including neuronal and glial cells in culture. It has been suggested that this effect may be due, at least partially, to inhibition of the isoprenoid pathway with blocking of isoprenylation of proteins involved in regulating cell proliferation and survival [110]. The
Conclusions
Statins reduce stroke in patients with pre-existing cardiovascular disease. In addition, this class of drugs may possess additional properties that prevent or limit the effects of ischemia on the brain vasculature and parenchyma, though at present evidence to support this idea is preliminary. There are some data to suggest that these effects are in part related to intermediates in the biosynthesis of cholesterol. The results from ongoing clinical studies should provide further information on
References (112)
- et al.
Current status of risk factors for stroke
Neurol. Clin.
(1983) - et al.
Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St. Thomas' Atherosclerosis Regression Study (STARS)
Lancet
(1992) - et al.
Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization
Am. J. Med.
(1998) - et al.
HMG-CoA reductase inhibitors suppress macrophage growth induced by oxidized low density lipoprotein
Atherosclerosis
(1997) - et al.
The effects of diet and lovastatin on regression of fatty streak lesions and on hepatic and intestinal mRNA levels for the LDL receptor and HMG CoA reductase in F1B hamsters
Atherosclerosis
(1998) - et al.
Inhibitory effect of fluvastatin at doses insufficient to lower serum lipids on the catheter-induced thickening of intima in rabbit femoral artery
Eur. J. Pharmacol.
(1996) - et al.
Proapoptotic effect of atorvastatin on stimulated rabbit smooth muscle cells
Pharmacol. Res.
(1997) - et al.
Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II)
Am. J. Cardiol.
(1995) - et al.
Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients
Atherosclerosis
(1989) - et al.
Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia
J. Am. Coll. Cardiol.
(1999)
Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile
J. Am. Coll. Cardiol.
Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia
Brain Res.
Expression of heme oxygenase and inducible nitric oxide synthase mRNA in human brain tumors
Biochem. Biophys. Res. Commun.
Role of endothelial dysfunction in coronary artery disease and implications for therapy
Am. J. Cardiol.
Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia
Atherosclerosis
HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia
J. Am. Coll. Cardiol.
Lovastatin reduces expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells
Biochem. Pharmacol.
Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine
J. Am. Coll. Cardiol.
Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL
Atherosclerosis
Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation
Atherosclerosis
The effect of Simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolaemia
Clin. Chim. Acta
Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study
Lancet
Intraneuronal beta-amyloid immunoreactivity in the CNS
Neurobiol. Aging
Genetic association studies between Alzheimer's disease and two polymorphisms in the low density lipoprotein receptor-related protein gene
Neurosci. Lett.
The effect of simvastatin on cerebrospinal fluid levels of apolipoprotein E in patients with Alzheimer's disease [abstract]
Atherosclerosis
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels
N. Engl. J. Med.
The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators
N. Engl. J. Med.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Lancet
Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group
N. Engl. J. Med.
Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study
JAMA
Cholesterol reduction in cardiovascular disease. Clinical benefits and possible mechanisms
N. Engl. J. Med.
Signaling molecules derived from the cholesterol biosynthetic pathway: mechanisms of action and possible roles in human disease
Curr. Opin. Lipidol.
Factors related to stroke incidence in Hawaii Japanese men. The Honolulu Heart Study
Stroke
Relation of blood pressure, serum lipids, and smoking to the risk of cerebral stroke. A longitudinal study in Eastern Finland
Stroke
Cerebrovascular disease in the bi-racial population of Evans County, Georgia
Stroke
Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Prospective studies collaboration
Lancet
Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial
N. Engl. J. Med.
Blood pressure, cholesterol, and stroke in eastern Asia
Lancet
Elevated serum cholesterol is a risk factor for both coronary heart disease and thromboembolic stroke in Hawaiian Japanese men. Implications of shared risk
Stroke
Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program
Stroke
Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators
Circulation
Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors
Stroke
Reductase inhibitor monotherapy and stroke prevention
Arch. Intern. Med.
Reduction of stroke events with pravastatin
Circulation
Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group
N. Engl. J. Med.
Clofibrate and niacin in coronary heart disease
JAMA
Pravastatin in the prevention of cerebrovascular disease and its consequences in the elderly: the PROSPER design [abstract]
Stroke
Major ongoing stroke trials: stroke prevention by aggressive reduction in cholesterol levels (SPARCL)
Stroke
MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience
Eur. Heart J.
Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B
N. Engl. J. Med.
Cited by (123)
Perspective insights of repurposing the pleiotropic efficacy of statins in neurodegenerative disorders: An expository appraisal
2021, Current Research in Pharmacology and Drug DiscoveryIntensive LDL-cholesterol lowering therapy and neurocognitive function
2017, Pharmacology and TherapeuticsNeuroprotection for traumatic brain injury
2015, Handbook of Clinical NeurologyCitation Excerpt :In addition, we also discuss some emerging multipotential strategies that show particular promise in preclinical TBI studies and warrant further investigation. The 3-hydroxy-3-methyglutaryl coenzyme A (HMGCoA) reductase inhibitors (statins) are inhibitors of cholesterol biosynthesis, but have additional pleiotropic properties (Cucchiara and Kasner, 2001) that make them potentially attractive neuroprotective agents (Wible and Laskowitz, 2010). At the microvasculature level, statins increase endothelium-derived nitric oxide production (Eto et al., 2002), reduce vascular inflammation (Maeda et al., 2003), and limit hemorrhagic stroke (Delanty et al., 2001); after experimental TBI, they reduce post-traumatic hypoperfusion and rebound hyperemia (Wang et al., 2007).