The geranylgeranyl‐transferase inhibitor GGTI‐286 does not reproduce rosuvastatin‐induced delayed preconditioning against oxygen‐glucose deprivation (OGD) in cultured rat cortical neurons

Abstract

Rosuvastatin (RST) has been recently shown to induce resistance against OGD via depletion of geranylgeranyl pyrophosphate (GGPP) rather than cholesterol levels in cultured neurons. RST also induces GGPP‐sensitive, reversible mitochondrial depolarization, decreased NADH/NADPH and ATP levels, and these alterations may contribute to the OGD‐resistant phenotype. Our purpose was to determine if pharmacological inhibition of protein geranylgeranylation with GGTI‐286 would reproduce the neuroprotective and metabolic effects of RST preconditioning.Primary cortical neuronal cultures were obtained from E18 Sprague‐Dawley rat fetuses, and were treated with GGTI‐286 (1–10μM) for 3 days before exposure to 3h OGD. GGTI‐286 did not provide protection against OGD. Cell viability determined 4 days after OGD (untreated vs. 5μM GGTI‐286, mean±SEM, n=8–32) was 34±1% vs. 39±1% of normoxic controls. Interestingly, GGTI‐286 (5μM) reduced mitochondrial membrane potential to 80±1%*, and neuronal NADH/NADPH to 79±3%* of control levels (*p<0.05, n=8–32) similarly to RST, but unlike RST, did not affect neuronal ATP levels. In summary, GGTI‐286 is able to replicate some but not all of the GGPP‐sensitive metabolic effects of RST and does not yield OGD resistance. Reduction in ATP levels appears to be crucial in RST‐induced preconditioning against OGD. Supported by OTKA K68976, K63401 and by NIH HL30260, HL65380, HL77731.