Anoxic-ischemic injury is a major cause of central nervous sytem dysfunction in the clinical settings of cardiac arrest and stroke. Recent studies from our own and other laboratories have provided strong support for the concept that excessive neuronal excitation is a critical mechanism is cell death from ischemia. We have demonstrated an attenuation of cell death in a rat model of global ischemia/reperfusion (""""""""cardiac arrest"""""""") by the blockade of cell excitation at the N-methyl-D-aspartate (NMDA)-preferring receptor using 2-amino-7-phosphonoheptanoic acid (AP-7). We have also shown a reduction in infarct size in a permanent arterial occlusion model of focal ischemia (""""""""stroke"""""""") in the rat using systemic administration of kynurenic acid, an inhibitor of cell excitation which is non-selective in regard to excitatory receptor subtype. Similar results were obtained with AP-7 when initial administration of the drug was delayed for 15 min post-occlusion. We therefore wish to extend and further delineate these observations by studying in these models the potential neuroprotective effects of these and other compounds, including not only competitive and noncompetitive NMDA antagonists but also non-NMDA antagonists and receptor-nonspecific antagonists as well. In addition, we wish to determine the maximun intervals between the ischemic insult and the administration of a neuroprotective drug which will still permit attenuation of the ischemic injury, in order to better define the time window of therapeutic intervention. Further, since NMDA-induced neuronal damage has been hypothesized to be linked to excessive calcium influx, the possible mechanism of pharmacologic protection will be studied by measuring both voltage-dependent and receptor- activated calcium influx in vitro and comparing these data to the neuroprotective effect of test compounds in vivo. Finally, the temporal and anatomic pattern of increased glucose uptake in the ischemic """"""""penumbra"""""""" of an infarct will be studied using the 2- deoxyglucose (2DG) autoradiographic technique in the arterial occlusion model to see if the patterns of increased 2-DG coincide with those of the zone of infarct attenuation effected by excitatory neurotransmitter antagonists in focal ischemia. This would be an important piece of supporting evidence for extending the excitotoxic hypothesis from global ischemia/reperfusion to focal ischemia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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University of California San Francisco
Schools of Medicine
San Francisco
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Thompson, Simon; Pearson, Andrea N; Ashley, Michelle D et al. (2011) Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection. J Biol Chem 286:19331-9
Zhou, An; Simon, Roger P; David, Larry (2011) Nascent proteomes of ischemic-injured and ischemic-tolerant neuronal cells. Int J Comput Biol Drug Des 4:40-55
Ordonez, Andrea Nicole; Jessick, Veronica Joy; Clayton, Corrin Erin et al. (2010) Rapid ischemic tolerance induced by adenosine preconditioning results in Bcl-2 interacting mediator of cell death (Bim) degradation by the proteasome. Int J Physiol Pathophysiol Pharmacol 2:36-44
Meller, Robert (2009) The role of the ubiquitin proteasome system in ischemia and ischemic tolerance. Neuroscientist 15:243-60
Loftus, Liam T; Gala, Rosaria; Yang, Tao et al. (2009) Sumo-2/3-ylation following in vitro modeled ischemia is reduced in delayed ischemic tolerance. Brain Res 1272:71-80
Meller, Robert; Thompson, Simon John; Lusardi, Theresa Ann et al. (2008) Ubiquitin proteasome-mediated synaptic reorganization: a novel mechanism underlying rapid ischemic tolerance. J Neurosci 28:50-9
Doyle, Kristian P; Yang, Tao; Lessov, Nikola S et al. (2008) Nasal administration of osteopontin peptide mimetics confers neuroprotection in stroke. J Cereb Blood Flow Metab 28:1235-48
Maysami, Samaneh; Lan, Jin Quan; Minami, Manabu et al. (2008) Proliferating progenitor cells: a required cellular element for induction of ischemic tolerance in the brain. J Cereb Blood Flow Metab 28:1104-13
Sato, Yu; Meller, Robert; Yang, Tao et al. (2008) Stereo-selective neuroprotection against stroke with vitamin A derivatives. Brain Res 1241:188-92
Thompson, Simon J; Loftus, Liam T; Ashley, Michelle D et al. (2008) Ubiquitin-proteasome system as a modulator of cell fate. Curr Opin Pharmacol 8:90-5

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