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 preconditioning.(IJPPP912002).
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 USA. Tel: (503) 413 2581, Fax: (503) 413 5465 E-mail: Rmeller@downeurobiology.org