Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones.
Statins [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] exert cholesterol-independent pleiotropic effects that include anti-thrombotic, anti-inflammatory, and anti-oxidative properties. Here, we examined direct protective effects of atorvastatin on neurones in different cell damage models in vitro. Primary cortical neurones were pre-treated with atorvastatin and then exposed to (i) glutamate, (ii) oxygen-glucose deprivation or (iii) several apoptosis-inducing compounds. Atorvastatin significantly protected from glutamate-induced excitotoxicity as evidenced by propidium iodide staining, nuclear morphology, release of lactate dehydrogenase, and mitochondrial tetrazolium metabolism, but not from oxygen-glucose deprivation or apoptotic cell death. This anti-excitototoxic effect was evident with 2-4 days pre-treatment but not with daily administration or shorter-term pre-treatment. The protective properties occurred independently of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition because co-treatment with mevalonate or other isoprenoids did not reverse or attenuate neuroprotection. Atorvastatin attenuated the glutamate-induced increase of intracellular calcium, which was associated with a modulation of NMDA receptor function. Taken together, atorvastatin exerts specific anti-excitotoxic effects independent of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition, which has potential therapeutic implications.
Bösel
Julian
J
Klinik und Poliklinik für Neurologie, Charité- Universitätsmedizin Berlin, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany.
Gandor
Florin
F
Harms
Christoph
C
Synowitz
Michael
M
Harms
Ulrike
U
Djoufack
Pierre Chryso
PC
Megow
Dirk
D
Dirnagl
Ulrich
U
Hörtnagl
Heide
H
Fink
Klaus B
KB
Endres
Matthias
M
D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000069059:Atorvastatin; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007003:Hypoglycemia / Q000188:drug therapy / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism
D000214:Acyl Coenzyme A; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011758:Pyrroles; D017470:Receptors, Glutamate; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D018698:Glutamic Acid; D000069059:Atorvastatin; D005947:Glucose