Ischemic Tolerance in an In Vivo Model of Glutamate “Preconditioning”

Abstract

Ischemia initiates a complicated biochemical cascade of events that triggers neuronal death. In this study, we focused on glutamate –mediated neuronal tolerance to ischemia-reperfusion. We employed an animal model of life-long excess release of glutamate, the glutamate dehydrogenase 1 transgenic (Tg) mouse, as a model of in vivo “glutamate preconditioning”. Nine- and 22-month old Tg and wild type (wt) mice were subjected to 90 min of middle cerebral artery occlusion followed by 24 hr reperfusion. The Tg mice suffered significantly reduced infarction and edema volume, compared with their wt counterparts. We further analyzed proteasomal activity, level of ubiquitin immunostaining, and MAP2A expression to understand the mechanism of neuroprotection observed in the Tg Mice. We found that in the absence of ischemia, the Tg mice exhibited higher activity of the 20S and 26S proteasomes while there were no significant differences in the level of hippocampal ubiquitin immunostaining between wt and Tg mice. A surprising observation was that of a significant increase in MAP2A expression in neurons of the Tg hippocampus following ischemia-reperfusion, compared with that in wt hippocampus. The results suggest that increased proteasome activity and MAP2A synthesis and transport might account for the effectiveness of glutamate preconditioning against ischemia-reperfusion.