Rosuvastatin induces delayed preconditioning against oxygen-glucose deprivation in cultured cortical neurons.
We tested whether rosuvastatin (RST) protected against oxygen-glucose deprivation (OGD)-induced cell death in primary rat cortical neuronal cultures. OGD reduced neuronal viability (%naive controls, mean +/- SE, n = 24-96, P < 0.05) to 44 +/- 1%, but 3-day pretreatment with RST (5 microM) increased survival to 82 +/- 2% (P < 0.05). One-day RST treatment was not protective. RST-induced neuroprotection was abolished by mevalonate or geranylgeranyl pyrophosphate (GGPP), but not by cholesterol coapplication. Furthermore, RST-induced decreases in neuronal cholesterol levels were abolished by mevalonate but not by GGPP. Reactive oxygen species (ROS) levels were reduced in RST-preconditioned neurons after OGD, and this effect was also reversed by both mevalonate and GGPP. These data suggested that GGPP, but not cholesterol depletion, were responsible for the induction of neuroprotection. Therefore, we tested whether 3-day treatments with perillic acid, a nonspecific inhibitor of both geranylgeranyl transferase (GGT) GGT 1 and Rab GGT, and the GGT 1-specific inhibitor GGTI-286 would reproduce the effects of RST. Perillic acid, but not GGTI-286, elicited robust neuronal preconditioning against OGD. RST, GGTI-286, and perillic acid all decreased mitochondrial membrane potential and lactate dehydrogenase activity in the cultured neurons, but only RST and perillic acid reduced neuronal ATP and membrane Rab3a protein levels. In conclusion, RST preconditions cultured neurons against OGD via depletion of GGPP, leading to decreased geranylgeranylation of proteins that are probably not isoprenylated by GGT 1. Reduced neuronal ATP levels and ROS production after OGD may be directly involved in the mechanism of neuroprotection.
Domoki
Ferenc
F
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA. domoki@phys.szote.u-szeged.hu
Kis
Béla
B
Gáspár
Tamás
T
Snipes
James A
JA
Parks
John S
JS
Bari
Ferenc
F
Busija
David W
DW
D000255:Adenosine Triphosphate / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D053138:Cyclohexenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency*; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D020826:rab3A GTP-Binding Protein / Q000378:metabolism
D053138:Cyclohexenes; D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; C437105:GGTI 286; D039821:Monoterpenes; D018696:Neuroprotective Agents; D011106:Polyisoprenyl Phosphates; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C078706:perillic acid; D000068718:Rosuvastatin Calcium; D000255:Adenosine Triphosphate; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; C083291:geranylgeranyltransferase type-I; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D020826:rab3A GTP-Binding Protein; D005978:Glutathione; D007930:Leucine; D005947:Glucose; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid