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J Neuropathol Exp Neurol. 2010 Mar;69(3):224-33. doi: 10.1097/NEN.0b013e3181cfc46f.

Adenoviral gene delivery of pigment epithelium-derived factor protects striatal neurons from quinolinic acid-induced excitotoxicity.

Author information

1
Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo, Japan.

Abstract

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.

PMID:
20142768
DOI:
10.1097/NEN.0b013e3181cfc46f
[Indexed for MEDLINE]

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