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Statine zur Behandlung von Erkrankungen des zentralen Nervensystems

Eine Standortbestimmung aus Forschung und Klinik

Statins for treatment of CNS diseases

Status report from research and clinical practice

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Zusammenfassung

3-Hydroxy-3-Methyglutaryl-Coenzym-A (HMG-CoA)-Reduktase-Inhibitoren, die so genannten „Statine“, sind oral verfügbaren Cholesterinsenker. Sie blockieren die Synthese von L-Mevalonat aus HMG-CoA, einem zentralen Zwischenprodukt der Cholesterinsynthese. Bestimmte L-Mevalonat-Metaboliten werden zudem für die posttranslationale Modifikation von Proteinen benötigt, die nötig für die Zellproliferation und -differenzierung sind. Somit nehmen Statine unabhängig von ihrem cholesterinsenkenden Effekt Einfluss auf wichtige biologische Mechanismen. Im Folgenden werden die potenzielle Anwendung von Statinen bei drei Erkrankungen des zentralen Nervensystems (ZNS) diskutiert: der Multiplen Sklerose (MS), der Demenz vom Alzheimer-Typ (DAT) und dem ischämischen Schlaganfall. Obwohl pathogenetisch hinreichend unterschiedlich, konnte in den entsprechenden Tiermodellen die Wirksamkeit von Statinen belegt werden, die zumeist auf cholesterinunabhängigen Mechanismen beruhen. Für die DAT und den Schlaganfall gibt es bereits Hinweise aus klinischen Fall-Kontroll-Studien über eine Wirksamkeit beim Menschen. Bei der MS liegen positive Ergebnisse aus zwei offenen, nichtplazebokontrollierten Studien vor. Derzeit sind für alle drei Erkrankungen multizentrische, randomisierte, plazobokontrollierte Studien in der Planungs- oder Rekrutierungsphase, um die klinische Wirksamkeit von Statinen zu belegen.

Summary

3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, “statins,” are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of L-mevalonate are also involved in posttranslational modifications of specific proteins with cell proliferation and differentiation properties. Thus, statins have important biologic effects beyond their cholesterol-reducing properties. Here we discuss recent experimental and clinical data that may support a potential role for statins in the treatment of three central nervous system (CNS) neurological diseases: Multiple sclerosis (MS), Alzheimer’s disease (AD), and ischemic stroke. Despite their considerable pathogenic differences, in animal models of these disorders statins have shown beneficial effects. In both stroke and AD cohort studies suggest a beneficial treatment effect in humans; in MS, results from small open-label studies look encouraging. Multicenter, randomized, placebo-controlled clinical trials are in the planning or recruiting stage to evaluate the therapeutic effects of statins in all three disorders.

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Danksagung

Dr. Til Menge ist ein Stipendiat der amerikanischen National Multiple Sclerosis Society. Dr. Scott Zamvil wird vom National Institute of Health sowie von der Alexander M. and June L. Maisin Foundation, der Wadsworth Foundation und der Nancy Davis Foundation unterstützt.

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  1. Department of Neurology, University of California, San Francisco, USA

    T. Menge & S. S. Zamvil

  2. Neurologische Klinik, Universitätsspital Zürich, Schweiz

    H.-C. von Büdingen

  3. Neurologische Klinik, Universität Düsseldorf

    H.-P. Hartung, B. C. Kieseier &  O. Stüve

  4. Neurologische Klinik, Heinrich-Heine-Universität, Moorenstraße 50, 40217, Düsseldorf, Deutschland

    O. Stüve

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  1. T. Menge
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Menge, T., von Büdingen, HC., Zamvil, S.S. et al. Statine zur Behandlung von Erkrankungen des zentralen Nervensystems . Nervenarzt 76, 426–437 (2005). https://doi.org/10.1007/s00115-004-1806-4

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