Rosuvastatin induces delayed preconditioning against L-glutamate excitotoxicity in cultured cortical neurons.
We tested whether rosuvastatin (RST) protected against excitotoxic neuronal cell death in rat primary cortical neuronal cultures. L-glutamate (200 microM, 1h) reduced neuronal viability (% of naive controls, mean+/-SEM, n=8-32, *p<0.05) from 100+/-2% to 60+/-1%*, but pretreatment with RST (0.5 microM, 3 days) increased survival to 88+/-2%*. RST-induced neuroprotection was not affected by co-application with mevalonate (10 microM), although the same dose of mevalonate fully prevented the neurotoxic effects of a high dose (20 microM) of RST. RST (0.5 microM) pretreatment did not affect mitochondrial membrane potential or superoxide anion levels in quiescent neurons. However, RST pretreatment blunted elevations in free intracellular Ca(2+) and reduced increases in superoxide anion levels following glutamate exposure. Manganese superoxide dismutase (SOD), copper-zinc SOD, catalase, and reduced glutathione levels were unaffected by RST pretreatment. In contrast, acute, one time RST application did not affect either baseline or L-glutamate-induced increases in superoxide levels. In summary, three-day RST pretreatment induces resistance to the excitotoxic effect of L-glutamate in cultured neurons apparently by a mechanism that is independent of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibition. The delayed neuroprotection by RST against excitotoxicity does not involve sustained mitochondrial depolarization or superoxide anion production as initiating events, although it is associated with reduced Ca(2+) influx and superoxide anion production upon L-glutamate challenge.
Domoki
Ferenc
F
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157-1010, USA. domoki@phys.szote.u-szeged.hu
Kis
Béla
B
Gáspár
Tamás
T
Snipes
James A
JA
Bari
Ferenc
F
Busija
David W
DW
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005464:Fluorobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019194:Ischemic Preconditioning; D008798:Mevalonic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018384:Oxidative Stress / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013481:Superoxides; D018698:Glutamic Acid; D000068718:Rosuvastatin Calcium; D008798:Mevalonic Acid; D002118:Calcium