title: Rosuvastatin-induced neuroprotection in cortical neurons exposed to OGD/reoxygenation is due to nitric oxide inhibition and ERK1/2 pathway activation.
abstract: The aim of the present study was to investigate the molecular mechanisms underlying the neuroprotective effect of the hydrophilic statin rosuvastatin on cortical neurons exposed to oxygen and glucose deprivation (OGD) followed by reoxygenation. Rosuvastatin (RSV), at concentrations ranging from 10 nM to 1μM, was able to ameliorate the survival of cortical neurons exposed to OGD followed by reoxygenation. This effect was observed either if neurons were pretreated with RSV 24 hrs before OGD/reoxygenation exposure or if RSV was added during the OGD or the reoxygenation phase. Moreover, RSV was also able to improve mitochondrial oxidative capacity in basal conditions, an effect that was already observed at 10 nM either after 24 or after 48 hrs of treatment. These neuroprotective actions were not counteracted by mevalonate, an intermediate of cholesterol biosynthesis that bypasses RSV induced blockade of cholesterol synthesis. Furthermore, the hypothesis that RSV might affect neuronal nitric oxide synthase (nNOS) activity during OGD/reoxygenation was explored. RSV was able to reduce the increase of NO occurring during the reoxygenation phase, an effect prevented by NPLA, the selective inhibitor of nNOS. Finally, the possibility that RSV-induced NO reduction during OGD/reoxygenation might involve ERK1/2 activation was also investigated. The treatment of neurons with PD98059, an ERK1/2 kinase inhibitor, abolished the neuroprotective effect exerted by RSV in cortical neurons exposed to OGD/reoxygenation. In conclusion, these results demonstrated that RSV-induced neuroprotection involves an impairment of constitutive and inducible NOS activity which in turn causes the improvement of mitochondrial function and the stimulation of ERK1/2 via H-Ras activation.
authors.forename: Claudia
authors.initials: C
authors.lastname: Savoia
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Sisalli
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
authors.forename: Antonella
authors.initials: A
authors.lastname: Scorziello