Statins induce differentiation and cell death in neurons and astroglia.
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.
März
Pia
P
Institute of Physiology, University of Basel, CH-4056 Basel, Switzerland.
Otten
Uwe
U
Miserez
André R
AR
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000069059:Atorvastatin; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002784:Cholesterol / Q000096:biosynthesis; D018920:Coculture Techniques; D004224:Diterpenes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006538:Heptanoic Acids / Q000627:therapeutic use / Q000633:toxicity; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D019821:Simvastatin / Q000627:therapeutic use / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004224:Diterpenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D011973:Receptors, LDL; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid