ZAFES Projects: Internal/External



New Targets of HMG-CoA Reductase Inhibitors (Statins) in the Central Nervous System

Statins are potent inhibitors of the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase a key enzyme of the cellular cholesterol synthesis. They can induce comparatively large reductions in plasma cholesterol levels and are well proven drugs for the treatment of hypercholesterolaemia. Although the pharmacology of statins is well established for the peripheral system, data about their effects in the central nervous system (CNS) are still lacking. Clinical and epidemiological findings indicate prevention of stroke and possibly a beneficial effect on the progression of Alzheimer’s Disease (AD). Hence, statins are considered a promising drug in the CNS. Abnormal processing of amyloid precursor protein (APP) in the AD brain results in deposits of neurotoxic ß-amyloid (Aß) that represents one pathological hallmark of this disease. Statins lower the amyloidogenic processing of APP in vitro and in vivo. This effect is linked to the cellular cholesterol homeostasis, since reducing membrane cholesterol lowers the amyloidogenic processing of APP in vitro. Thus, statins lower the risk of AD by reducing Aß. However, statins’ mode of action in the CNS is not well understood yet. The consortium under the ZAFES network aims to elucidate the pharmacological basis for the central effects of statins observed in AD and stroke. Our approach involves the investigation of pathomolecular mechanisms, drug analytics, in vitro and in vivo studies, and gene expression profiling. Elucidation of pathomolecular mechanisms and effects of statins on brain lipid homeostasis are assessed by the Institute of Interdisciplinary Pharmacology (Prof. Müller, ZAFES). The Institute of Pharmaceutical Chemistry, together with an industrial partner, applies a recently developed rapid high performance liquid chromatography coupled with tandem mass spectroscopy using electrospray ionisation to assess brain availability and brain concentrations reached after pharmacological doses of statins (Prof. Schubert-Zsilavecz, Prof. Karas, ZAFES; Dr. Fechner, Applied Biosystems, Darmstadt). AD-related animal models are provided by Aventis (Dr. Benavides, Dr. Pradier, Paris). The University of Minnesota adds gene expression pattern analysis of the brain (Prof. Wood, VA Medical Center, Minneapolis) [Figure]. The consortium aims to discover underlying mechanisms to better understood the potential therapeutic efficacy of statins in AD and possibly other neurodegenerative diseases.

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