IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2011;3(1):57-64

Original Article
Rosuvastatin-induced neuroprotection in cortical neurons exposed to
OGD/reoxygenation is due to nitric oxide inhibition and ERK1/2 pathway activation

Claudia Savoia, Maria Josè Sisalli, Gianfranco Di Renzo, Lucio Annunziato, Antonella Scorziello

Division of Pharmacology, Department of Neuroscience, School of Medicine Federico II, University of Naples, Via S. Pansini 5, 80131
Naples, Italy; National Institute of Neuroscience (INN) Corso Raffaello 3010125 Torino, Italy; Fondazione IRCCS SDN, Naples, Italy.

Received December 28, 2010; accepted January 5, 2011; Epub January 6, 2011; Published January 10, 2011

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 10nM to 1M, 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. (IJPPP1012005).

Key words: Cortical neurons, oxygen glucose deprivation/reoxygenation, nitric oxide, ERK1/2, mitochondria, cell death

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Address all correspondence to:
Antonella Scorziello, MD, PhD
Associate Professor of Pharmacology
Division of Pharmacology,
Department of Neuroscience,
School of Medicine, “Federico II” University of Naples
Via S. Pansini 5, 80131 Naples, Italy
Phone: +39 081 7463330; Fax: +39 081 7463323
E-mail:
scorziel@unina.it