title: Ischemic tolerance in an in vivo model of glutamate preconditioning.
abstract: Ischemia initiates a complicated biochemical cascade of events that triggers neuronal death. This study focuses on glutamate-mediated neuronal tolerance to ischemia-reperfusion. We employed an animal model of lifelong excess release of glutamate, the glutamate dehydrogenase 1 transgenic (Tg) mouse, as a model of in vivo glutamate preconditioning. Nine- and twenty-two-month-old Tg and wild-type (wt) mice were subjected to 90 min of middle cerebral artery occlusion, followed by 24 hr of 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 microtubule-associated protein-2A (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, whereas there was no significant difference in the level of hippocampal ubiquitin immunostaining between wt and Tg mice. A surprising, significant increase was observed 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.
authors.affiliation: Neuroscience Program, University of Kansas, Lawrence, Kansas; Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas.
authors.forename: Yomna
authors.initials: Y
authors.lastname: Badawi
authors.forename: Ranu
authors.initials: R
authors.lastname: Pal
authors.forename: Dongwei
authors.initials: D
authors.lastname: Hui
authors.forename: Elias K
authors.initials: EK
authors.lastname: Michaelis
authors.forename: Honglian
authors.initials: H
authors.lastname: Shi
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema; D020520:Brain Infarction / Q000209:etiology; D002545:Brain Ischemia / Q000235:genetics / Q000517:prevention & control*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005969:Glutamate Dehydrogenase; D018698:Glutamic Acid / Q000008:administration & dosage*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; D025801:Ubiquitin; D018698:Glutamic Acid; C570817:GluD1 protein, mouse; D005969:Glutamate Dehydrogenase; D046988:Proteasome Endopeptidase Complex
keywords: MAP2; aging; hippocampus; stroke; ubiquitin