Astrocyte targeted overexpression of Hsp72 or SOD2 reduces neuronal vulnerability to forebrain ischemia.
Brief forebrain ischemia is a model of the delayed hippocampal neuronal loss seen in patients following cardiac arrest and resuscitation. Previous studies demonstrated that selective dysfunction of hippocampal CA1 subregion astrocytes occurs hours to days before delayed neuronal death. In this study we tested the strategy of directing protection to astrocytes to protect neighboring neurons from forebrain ischemia. Two well-studied protective proteins, heat shock protein 72 (Hsp72) or superoxide dismutase 2 (SOD2), were genetically targeted for expression in astrocytes using the astrocyte-specific human glial fibrillary acidic protein (GFAP) promoter. The expression constructs were injected stereotacticly immediately above the hippocampal CA1 region on one side of the rat brain two days prior to forebrain ischemia. Cell type specific expression was confirmed by double label immunohistochemistry. When the expression constructs were injected two days before transient forebrain ischemia, the loss of CA1 hippocampal neurons observed seven days later was significantly reduced on the injected side compared with controls. This neuroprotection was associated with significantly better preservation of astrocyte glutamate transporter-1 immunoreactivity at 5-h reperfusion and reduced oxidative stress. Improving the resistance of astrocytes to ischemic stress by targeting either the cytosolic or mitochondrial compartment was thus associated with preservation of CA1 neurons following forebrain ischemia. Targeting astrocytes is a promising strategy for neuronal preservation following cardiac arrest and resuscitation.
Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305-5117, USA.
Lijun
L
Xu
John F
JF
Emery
Yi-Bing
YB
Ouyang
Ludmila A
LA
Voloboueva
Rona G
RG
Giffard
D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D002545:Brain Ischemia / Q000503:physiopathology*; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D011401:Promoter Regions, Genetic; D016548:Prosencephalon / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099156:Superoxide Dismutase 2
D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D050884:HSP72 Heat-Shock Proteins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2