Induction of GRP78 by ischemic preconditioning reduces endoplasmic reticulum stress and prevents delayed neuronal cell death.
Although the endoplasmic reticulum (ER) is implicated in neuronal degeneration in some situations, its role in delayed neuronal cell death (DND) after ischemia remains uncertain. The authors speculated that ER stress is involved in DND, that it is reduced by ischemic preconditioning, and that ER stress reduction by preconditioning is due to ER molecular chaperone induction. The phosphorylation status of eukaryotic initiation factor 2alpha (eIF2alpha) and RNA-dependent protein kinase-like ER eIF2alpha kinase (PERK) was investigated in the rat hippocampus after ischemia with and without preconditioning. PERK is phosphorylated by ER stress, which phosphorylates eIF2alpha. To investigate the role of ER molecular chaperones in preconditioning, the authors examined GRP78 and GRP94 expression, both of which are ER chaperones that inhibit PERK phosphorylation, and compared their induction and ischemic tolerance time windows. Phosphorylation of eIF2alpha and PERK was confirmed after severe ischemia but was inhibited by preconditioning. After preconditioning, GRP78 was increased in the brain with a peak at 2 days, which corresponded with the ischemic tolerance time window. Immunoprecipitation and double staining demonstrated involvement of GRP78 in prevention of PERK phosphorylation. These results suggest that GRP78 induced by preconditioning may reduce ER stress and eventual DND after ischemia.
Hayashi
Takeshi
T
Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California 94305, U.S.A.
Saito
Atsushi
A
Okuno
Shuzo
S
Ferrand-Drake
Michel
M
Chan
Pak H
PH
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D016923:Cell Death / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006360:Heat-Shock Proteins; D006624:Hippocampus / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019194:Ischemic Preconditioning; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D018832:Molecular Chaperones / Q000096:biosynthesis*; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D011233:Precipitin Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D019892:eIF-2 Kinase / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
D002352:Carrier Proteins; D015852:Eukaryotic Initiation Factor-2; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D019892:eIF-2 Kinase; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C018551:glucose-regulated proteins