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Statins induce differentiation and cell death in neurons and astroglia
Glia, 2007-01, Vol.55 (1), p.1-12
März, Pia
Otten, Uwe
Miserez, André R.
2007
Details
Autor(en) / Beteiligte
März, Pia
Otten, Uwe
Miserez, André R.
Titel
Statins induce differentiation and cell death in neurons and astroglia
Ist Teil von
Glia, 2007-01, Vol.55 (1), p.1-12
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2007
Link zum Volltext
Quelle
Wiley Online Library Journals【キャンパス外アクセス可】
Beschreibungen/Notizen
Statins are potent inhibitors of the hydroxy‐methyl‐glutaryl‐coenzyme A reductase, the rate limiting enzyme for cholesterol biosynthesis. Experimental and clinical studies with statins suggest that they have beneficial effects on neurodegenerative disorders. Thus, it was of interest to characterize the direct effects of statins on CNS neurons and glial cells. We have treated defined cultures of neurons and astrocytes of newborn rats with two lipophilic statins, atorvastatin and simvastatin, and analyzed their effects on morphology and survival. Treatment of astrocytes with statins induced a time‐ and dose‐dependent stellation, followed by apoptosis. Similarly, statins elicited programmed cell death of cerebellar granule neurons but with a higher sensitivity. Analysis of different signaling cascades revealed that statins fail to influence classical pathways such as Akt or MAP kinases, known to be activated in CNS cells. In addition, astrocyte stellation triggered by statins resembled dibutryl‐cyclic AMP (db‐cAMP) induced morphological differentiation. However, in contrast to db‐cAMP, statins induced upregulation of low‐density lipoprotein receptors, without affecting GFAP expression, indicating separate underlying mechanisms. Analysis of the cholesterol biosynthetic pathway revealed that lack of mevalonate and of its downstream metabolites, mainly geranylgeranyl‐pyrophosphate (GGPP), is responsible for the statin‐induced apoptosis of neurons and astrocytes. Moreover, astrocytic stellation triggered by statins was inhibited by mevalonate and GGPP. Interestingly, neuronal cell death was significantly reduced in astrocyte/neuron co‐cultures treated with statins. We postulate that under these conditions signals provided by astrocytes, e.g., isoprenoids play a key role in neuronal survival. © 2006 Wiley‐Liss, Inc.
Sprache
Englisch
Identifikatoren
ISSN: 0894-1491
eISSN: 1098-1136
DOI: 10.1002/glia.20422
Titel-ID: cdi_proquest_miscellaneous_19352355
Format
–
Schlagworte
Animals
,
Animals, Newborn
,
Apoptosis - drug effects
,
Apoptosis - physiology
,
astrocyte
,
Astrocytes - drug effects
,
Astrocytes - metabolism
,
Astrocytes - pathology
,
Atorvastatin Calcium
,
brain
,
Cell Communication - physiology
,
Cell Differentiation - drug effects
,
Cell Differentiation - physiology
,
Cell Shape - drug effects
,
Cell Shape - physiology
,
Cell Survival - drug effects
,
Cell Survival - physiology
,
Cells, Cultured
,
Central Nervous System - drug effects
,
Central Nervous System - metabolism
,
Central Nervous System - physiopathology
,
cholesterol
,
Cholesterol - biosynthesis
,
Coculture Techniques
,
cytotoxicity
,
Diterpenes - metabolism
,
Dose-Response Relationship, Drug
,
Heptanoic Acids - therapeutic use
,
Heptanoic Acids - toxicity
,
HMG-CoA reductase inhibitor
,
Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use
,
Hydroxymethylglutaryl-CoA Reductase Inhibitors - toxicity
,
isoprenoids
,
Mevalonic Acid - metabolism
,
Mevalonic Acid - pharmacology
,
Neurons - drug effects
,
Neurons - metabolism
,
Neurons - pathology
,
Polyisoprenyl Phosphates - metabolism
,
Pyrroles - therapeutic use
,
Pyrroles - toxicity
,
rat
,
Rats
,
Rats, Wistar
,
Receptors, LDL - drug effects
,
Receptors, LDL - metabolism
,
Simvastatin - therapeutic use
,
Simvastatin - toxicity
,
stellation
,
sterol-regulatory element binding protein
,
Up-Regulation - drug effects
,
Up-Regulation - physiology
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