52
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Molecular Mechanisms Underlying the Effects of Statins in the Central Nervous System

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly referred to as statins, are widely used in the treatment of dyslipidaemia, in addition to providing primary and secondary prevention against cardiovascular disease and stroke. Statins’ effects on the central nervous system (CNS), particularly on cognition and neurological disorders such as stroke and multiple sclerosis, have received increasing attention in recent years, both within the scientific community and in the media. Current understanding of statins’ effects is limited by a lack of mechanism-based studies, as well as the assumption that all statins have the same pharmacological effect in the central nervous system. This review aims to provide an updated discussion on the molecular mechanisms contributing to statins’ possible effects on cognitive function, neurodegenerative disease, and various neurological disorders such as stroke, epilepsy, depression and CNS cancers. Additionally, the pharmacokinetic differences between statins and how these may result in statin-specific neurological effects are also discussed.

          Related collections

          Most cited references140

          • Record: found
          • Abstract: found
          • Article: not found

          Structural mechanism for statin inhibition of HMG-CoA reductase.

          HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.

            Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.
              Bookmark
              • Record: found
              • Abstract: not found
              • Article: not found

              A receptor-mediated pathway for cholesterol homeostasis.

                Bookmark

                Author and article information

                Contributors
                Role: External Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                10 November 2014
                November 2014
                : 15
                : 11
                : 20607-20637
                Affiliations
                [1 ]School of Pharmacy, Griffith University, Queensland 4222, Australia; E-Mails: a.mcfarland@ 123456griffith.edu.au (A.J.M.); s.dukie@ 123456griffith.edu.au (S.A.-D.); d.arora@ 123456griffith.edu.au (D.S.A.); g.grant@ 123456griffith.edu.au (G.D.G.)
                [2 ]Griffith Health Institute, Griffith University, Queensland 4222, Australia; E-Mail: a.perkins@ 123456griffith.edu.au
                [3 ]Department of Biomedical Science, Bond University, Queensland 4226, Australia; E-Mail: camcderm@ 123456bond.edu.au
                [4 ]School of Medical Sciences, Griffith University, Queensland, 4222, Australia
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: a.davey@ 123456griffith.edu.au ; Tel.: +61-7555-28361; Fax: +61-7555-28804.
                Article
                ijms-15-20607
                10.3390/ijms151120607
                4264186
                25391045
                75552414-dffe-44cb-921a-992ca38fcab3
                © 2014 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 September 2014
                : 23 October 2014
                : 30 October 2014
                Categories
                Review

                Molecular biology
                statin,cognition,central nervous system (cns),neurotoxicity,neuroprotection
                Molecular biology
                statin, cognition, central nervous system (cns), neurotoxicity, neuroprotection

                Comments

                Comment on this article