Adenoviral gene delivery of pigment epithelium-derived factor protects striatal neurons from quinolinic acid-induced excitotoxicity.
The 50-kDa secreted glycoprotein pigment epithelium-derived factor (PEDF) is neuroprotective for various types of cultured neurons, but whether it is neuroprotective for neurons in vivo is not known. We examined the effects of adenovirus-mediated gene transfer of PEDF on quinolinic acid (QA)-induced neurotoxicity in rats. Adenoviral vector containing the human PEDF gene (Ad.PEDF) or Escherichia coli beta-galactosidase gene (Ad.LacZ) was directly injected into the right striatum 7 days before the injection of QA. Immunohistochemical analysis using antibodies specific for the neuronal markers dopamine and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa, neuronal nuclei, and choline acetyltransferase revealed that the QA-induced striatal damage was significantly reduced in Ad.PEDF-treated rats. Overexpression of PEDF also reduced the expression of the inflammation-related genes for interleukin 1beta, tumor necrosis factor alpha, and macrophage inflammatory protein 1alpha 1 day after QA injection. Deletion analysis of human PEDF protein demonstrated that overexpression of PEDFDelta44-121 failed to protect neurons against QA-induced excitotoxicity, whereas PEDFDelta78-121 retained the neuroprotective activity, suggesting that amino acid residues 44-77 of the PEDF sequence are essential for PEDF-mediated neuroprotection in vivo. These results provide the first evidence that PEDF and its deletion mutant PEDFDelta78-121 are effective in protecting CNS neurons against excitotoxicity in vivo.
Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo, Japan.
Tomomi
T
Sanagi
Takeshi
T
Yabe
Haruki
H
Yamada
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation / Q000235:genetics; D009414:Nerve Growth Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D010750:Phosphoproteins / Q000378:metabolism; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D015843:Serpins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D015415:Biomarkers; D002795:Choline O-Acetyltransferase; D016207:Cytokines; D004298:Dopamine; D005136:Eye Proteins; D009414:Nerve Growth Factors; D009498:Neurotoxins; D010750:Phosphoproteins; D017378:Quinolinic Acid; D017470:Receptors, Glutamate; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor