Use of statins in CNS disorders

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Abstract

It is well established that 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) reduce cholesterol levels and prevent coronary heart disease (CHD). Although a causal relation between elevated cholesterol levels and stroke has not been well defined, a number of large secondary prevention studies and meta-analyses have shown that statin therapy reduces stroke in patients with CHD and hypercholesterolemia. In addition to the vascular effects of statins (stabilization of atherosclerotic plaques, decreased carotid intimal–medial thickness), there are increasing data to suggest that these agents have additional properties that are potentially neuroprotective. These include endothelial protection via actions on the nitric oxide synthase system, as well as antioxidant, anti-inflammatory and anti-platelet effects. These actions of statins might have potential uses in other neurological disorders such as Alzheimer's disease and certain types of brain tumors.

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

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