Delayed preconditioning with rosuvastatin protects cultured rat cortical neurons against oxygen‐glucose deprivation and excitotoxicity

Abstract

Primary cortical neuronal cultures were obtained from E18 Sprague-Dawley rat fetuses, and were treated with rosuvastatin (RST, 10nM-100μM, 6 or 24h/day treatment for 1–5 days) before exposure to oxygen-glucose deprivation (OGD) or excitoxic insult (0.2 mM glutamate, 1h). RST ( 2 days treatment) exerted potent neuroprotection against both OGD and excitotoxic stress. 24h after 2h OGD, for instance, cell viability (% of controls, mean±SEM, n=8) significantly increased from 52±1% to 69±4, 77±4%, 90±4%, 98±5%, and 90±3% (3d treatment with 0.5, 1, 2, 3, and 5 μM RST, respectively, p<0.05). Higher doses of RST were neurotoxic. Cholesterol coapplication did not alter RST-induced neuroprotection. RST (1–5 μM) dose-dependently reduced cellular ATP levels after 3 but not 1-day treatment. Further, glutamate-or reoxygenation-induced reactive oxygen species (ROS) production detected with hydroethidine fluorescence was markedly reduced in the preconditioned cells. In summary, RST elicited robust delayed but not acute pharmacological preconditioning against OGD or glutamate-induced cell death in cultured neurons. The effect appears to be unrelated to the blockade of cholesterol biosynthesis. The altered cellular ATP levels and the reduced ROS production to stress suggest the involvement of mitochondria in the mechanism of protection afforded by the drug. Supported by HL-50587, HL-65380, HL-77731, and OTKA T046531.