PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Statins: The Miracle Drugs by Tahira Farooqui, Ph.D Department of Entomology The Ohio State University Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (a rate limiting enzyme in cholesterol biosynthesis), which catalyzes production of mevalonate from HMG-CoA to mevalonic acid. Thereby, inhibiting HMG-CoA reductase, statins not only reduce the synthesis of cholesterol but also inhibit synthesis of isoprenoid intermediates (see Figure 1). In addition to lowering cholesterol, statins also exert various ‘pleiotropic’ (non-lipid-lowering actions) and ‘vasculoprotective’ (such as stabilization of atherosclerotic plaques, increase in nitric oxide availability, upregulation of endothelial nitric oxide synthase, antioxidant, anti-inflammatory and immunomodulatory actions) effects on metabolic activities.  Click Figure 1 to view a larger image Cardiovascular disease mainly results from hypercholesterolemia. In addition to high cholesterol, there are other risk factors (such as hypertension, genetic factor, diabetes, stress, smoking, and overweight), that modulate atherogenesis. By inhibiting HMG-CoA reductase, statins are considered as principal and most effective drugs to reduce serum cholesterol levels in cardiac patients [1]. Therefore, withdrawl of statins from these patients may be dangerous because absence of this drug will impair vascular function. In brain, cholestrol is essential for neuronal viability and for neuronal and glial cell function. It affects physicochemical properties of neural membranes and thus regulates activities of membrane bound enzymes, receptors and ion channels. Disturbance in cholesterol homeostasis, has been implicated in neurodegenerative diseases (such as Niemann-Pick type C). Patients with elevated cholesterol have also been reported to show increased susceptibility to Alzheimer’s disease and it is believed that cholestrol is involved in the regulation of amyloid precursor protein processing. Although the precise mechanism(s) linking cholesterol to neurodegenerative diseases is not clearly understood but it is becoming increasingly evident that cholesterol oxidation products (such as 7-ketocholestrol, 6-ketocholestrol, 7-beta-hydroxycholestrol, 7-beta- hydroxycholestrol, 25-hydroxycholestrol, 6alpha-epoxide, and 6alpha-epoxide) possess mutagenic, cytotoxic, carcinogenic, angiotoxic and other membrane damaging properties. Hypothesis that neurodegeneration is mediated by cholesterol oxidation product has been recently tested. Thus the addition of cholesterol oxidation products to hippocampal slices results in neuronal injury. This effect can be attenuated by glutathione and other antioxidants suggesting the involvement of oxidative mechanisms by cholesterol oxidation products [2, 3]. It is likely that cholesterol oxidation products along with products of phospholipase A2-catalyzed reactions products such as arachidonic acid, eicosanoids, and 4-hydroxynonenal disrupt neuronal membrane integrity and alteration in membrane bound enzymes, receptors, and ion channels. These processes may result in neurodegeneration. Statins have demonstrated a significant reduction in ischemic stroke without an increase in hemorrhagic stroke [4]. Statins probably reduce stroke by number of mechanisms including modulation of precerebral atherothrombosis in the aorta and carotid artery, improvement of endothelial homeostasis by upregulating brain endothelial nitric oxide synthase and anti-inflammatory actions of the drug [5, 6]. Previous studies have suggested that hypercholesterolemia (elevated cholesterol) was not a risk factor for stroke. Then question arises why does statin therapy is used to reduce ischemic stroke in patients with vascular disease? Is it due to the cholesterol-independent action of statins? Vaughan (2003) has reviewed effects of statins beyond its lipid lowering actions by a variety of mechanisms involving depletion of isoprenoids after inhibiting HMG-CoA reductase [7]. A group of researchers has recently demonstrated that both endothelial nitric oxide synthase (eNOS) and endogenous tissue-type plasminogen activator (tPA) are key modulators of ischemic damage [8]. Clinical data also support the concept that statins when coadministered with angiotensin-converting enzyme (ACE) inhibitors may act synergistically to lower blood pressure [9]. Therefore, statins can reduce stroke risk in individuals who suffer with high blood pressure but do not have high cholesterol. These findings suggest that statins protect against stroke by multiple mechanisms including upregulation of eNOS and tPA, anti-oxidant and anti-inflammatory actions. Statins reduce intracellular and extracellular levels of beta-amyloid (Abeta) not only in primary cultures of hippocampal and mixed cortical neurons [9] but also in guinea pig brain. Alzheimer disease (AD) is characterized pathologically by deposition of extracellular Abeta and accumulation of neurofibrillary tangles. High cellular cholesterol content has been reported to increase Abeta synthesis by boosting beta-secretase activity [10]. Therefore, inhibition of cholesterol synthesis and/or stimulation of cholesterol export thus diminish deposition of Abeta [10]. AD and cardiovascular disease share a common risk factor, notably hypercholesterolemia. The excess cholesterol has also been reported to promote microglial activation, which increases production of inflammatory mediators further boosting Abeta production and inducing dysfunction and death of neurons [10]. Thus a simple strategy to delay the onset or biological progression of AD is to put patients on statin therapy. The results of recent studies indicate that the patients who were started on statin therapy showed reduced risk of AD [11]. This could be due to reduction of Abeta formation and deposition by statins. Statins are regarded as “miracle drugs” because of their above beneficial properties [1]. They are effectively used as cholesterol lowering agents. Recent studies have actually extended the use of statin therapy to the acute manifestations of cardiovascular disease. Due to their pleiotropic effects, statins have a wide scope for cardiovascular and cerebrovascular therapies. However, statins also have some adverse effects (such as gastrointestinal symptoms, headache, rash) which are relatively mild. Furthermore, at higher concentration, statins may also include severe side effects (such as myopathy, rehabdomylosis with renal failure). A number of drug-statin interactions may also result in muscle toxicity. Several statins are metabolized by cytochrome P455 isoenzymes. Therefore, they should not be taken with cytochrome P455 inhibitors (such as macrolide antibiotics, cyclosporine, HIV protease inhibitors, selective serotonin reuptake inhibitors and grapefruit juice). In cholesterol synthesis, mevalonate is not only the precursor for cholesterol, but it is also a precursor for non-sterol end-products such as dolichols and coenzyme Q indicating a common biosynthetic pathway associated with the synthesis of cholestrol as well as coenzyme Q. Coenzyme Q is an irreplaceable component of mitochondrial electron transport chain because it has ability to transfer electrons and therefore acts as an anti-oxidant and a membrane stabilizer. Since statins inhibit HMG-CoA reductase, therefore, they can also reduce the levels of coenzyme Q in serum as well as body tissues. On August 9, 2001, AG Bayer, a well known German pharmaceutical company has withdrawn the distribution of its product, Baycol (Lipobay) -a statin also known as cerivastatin- because of serious side effect (a condition called rhabdomyolysis) [10]. This is a rare side effect of all statin drugs that leads into a condition in which muscles are damaged. These adverse effects have caused the death of many patients wordwide. This condition occurs when statins are used in combination with other types of cholesterol lowering drugs, (e.g. gemfibrozil) or with drugs which increase the blood levels of statins. Since we are still unaware of long-term side effects of other statins, therefore many physicians recommend a combination of coenzyme Q and statins for cardiovascular therapy. References: 1. Topol EJ (2004) Intensive Statin therapy-a sea change in cardiovascular prevention. N Engl J Med 350: 1562-1564. 2. Ong WY, Goh EV, Lu XR, Farooqui AA, Patel SC, Halliwell B (2003) Increase in cholesterol and cholesterol oxidation products, and role of cholesterol oxidation products in kainite-induced neuronal injury. Brain Pathol 13: 250-262. 3. He X, Jenner AM, Ong WY, Farooqui AA, Patel SC (2006) Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainite injury. J Neuropathol Exp Neurol 65: 652-663 4. Gorelick PB (2002) Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stoke pathogenesis and implications for therapy. Stroke 33: 862-875. 5. Endres M (2005) Statins and stroke. J Cereb Blood Flow and Metab 25: 1093-1110. 6. Albert MA, Danielson E, Rifai N, Ridker PM; PRINCE Investigators (2001) Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA 286: 64-70. 7. Vaughan CJ (2003) Prevention of stroke and dementia with statins: effects beyond lipid lowering. Am J Cardiol 91suppl: 23B-29B. 8. Asahi M, Huang Z, Thomas S, Yoshimura SI, Sumii T, Mori T, Qiu J, Amin-Hanjani S, Huang PL, Liao JK, Lo EH, Moskowitz MA (2005) Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab 25: 722-729. 9. Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, von Bergmann K, Hennerici M, Beyreuther K and Hartmann T (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta–amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad USA 98: 5856-5861. 10. McCarty MF (2006) Toward prevention of Alzheimers disease- Potential nutraceutical strategies for suppressing the production of amyloid beta peptides. Med Hypotheses 67: 682-697. 11. DeKosky ST (2005) Statin therapy in the treatment of Alzheimer disease: what is the rationale? Am J Med 118 Suppl 12A: 48-53. 12. Bliznakov EG (2002) Lipid-lowering drugs (statins), cholesterol, and coenzyme Q10. The Baycol case – a modern Pandora’s box. Biomed Pharacother 56: 56-59. ### << Previous Next >> [ View All Perspectives ] |
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