Rosuvastatin Induces Delayed Preconditioning Against Oxygen-glucose Deprivation In Cultured Cortical Neurons
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1
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, United States
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2
Department of Physiology, University of Szeged, Hungary
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3
Department of Radiology , Harvard Medical School, United States
We examined if rosuvastatin (RST) preserved viability of primary rat cortical neuronal cultures after oxygen-glucose deprivation (OGD). OGD reduced neuronal viability (% of untreated controls, mean±SEM, n=24-96, *p<0.05) to 44±1%, but pretreatment with RST (3-day, 5 M) increased survival to 82±2%*. 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 non-specific 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 which 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.
Conference:
12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009.
Presentation Type:
Poster Presentation
Topic:
Pathophysiology and neurology - degenerative disorders
Citation:
Domoki
F,
Kis
B,
Gaspar
T,
Snipes
JA,
Bari
F and
Busija
DW
(2009). Rosuvastatin Induces Delayed Preconditioning Against Oxygen-glucose Deprivation In Cultured Cortical Neurons.
Front. Syst. Neurosci.
Conference Abstract:
12th Meeting of the Hungarian Neuroscience Society.
doi: 10.3389/conf.neuro.01.2009.04.148
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Received:
05 Mar 2009;
Published Online:
05 Mar 2009.
*
Correspondence:
Ferenc Domoki, Department of Physiology and Pharmacology, Wake Forest University Health Sciences, North Carolina, United States, domoki@phys.szote.u-szeged.hu