IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2010;2(1):36-44.

Original Article
Rapid ischemic tolerance induced by adenosine preconditioning results in Bcl-2
interacting mediator of cell death (Bim) degradation by the proteasome

Andrea Nicole Ordonez, Veronica Joy Jessick, Corrin Erin Clayton, Michelle Dawn Ashley, Simon John Thompson, Roger Pancoast
Simon, Robert Meller

Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA

Received December 10, 2009, accepted December 21, 2009, available online January 1, 2010

Abstract: Rapid ischemic tolerance, induced one hour following ischemic preconditioning, is mediated via the ubiq-uitin-proteasome
system and the degradation of the pro-apoptotic bcl-2 family protein Bim. Previous studies impli-cate adenosine A1 receptors in
mediating rapid ischemic tolerance. Since the A1 adenosine receptor antagonist DPCPX (10mM) blocked rapid ischemic tolerance in
our model, we investigated whether adenosine-mediated precon-ditioning induces rapid ischemic tolerance via the proteasomal
degradation of Bim. Cultured rat cortical neurons were incubated for 60 minutes with either adenosine (1mM) or
(-)-N6-(2-Phenyl-isopropyl) adenosine (RPIA (1mM)), prior to a harmful dose of ischemia (120 min oxygen and glucose deprivation).
Preconditioned cells had significantly lower levels of cell death following harmful ischemia when compared to non-preconditioned
cells. The proteasome inhibitor MG132 (0.1mM) blocked the protective effect of adenosine pre-conditioning. Immunoblot analysis
revealed a decrease in Bim protein levels in adenosine and RPIA preconditioned neurons. Adenosine preconditioning induced
neuroprotection and Bim degradation was blocked by the MEK inhibitor UO126 (10mM). Our data suggests that pharmacological
preconditioning with adenosine results in proteasomal Bim degradation mediated by p42/44 MAPK. Therefore, pharmacological
approaches may be able to induce rapid ischemic tolerance via similar molecular mecha-nisms as ischemic

Key words: Adenosine, rapid ischemic tolerance, Bcl-2, proteasome, ubiquitin

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Address all correspondence to:
Robert Meller, PhD
Robert S. Dow Neurobiology Laboratories
Legacy Clinical Research and Technology Center
1225 NE 2nd Avenue, Portland, OR 97232
Tel: (503) 413 2581, Fax: (503) 413 5465