The protective effect of hepatocyte growth factor against cell death in the hippocampus after transient forebrain ischemia is related to the improvement of apurinic/apyrimidinic endonuclease/redox factor-1 level and inhibition of NADPH oxidase activity.
Early oxidative DNA damage is regarded to be an initiator of neuronal apoptotic cell death after cerebral ischemia. Although evidence suggests that HGF has the ability to protect cells from oxidative stress, it remains unclear as to how HGF suppresses oxidative DNA damage after cerebral ischemia. Apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) is a multifunctional protein in the DNA base repair pathway that is responsible for repairing apurinic/apyrimidinic sites in DNA after oxidation. We demonstrated that both the immunoreactivity and the number of APE/Ref-1-positive cells in the hippocampal CA1 region were decreased after transient forebrain ischemia and that treatment with HGF suppressed this reduction. The expression of Cu/ZnSOD and MnSOD in the hippocampal CA1 region did not change after ischemia, regardless of treatment with or not with HGF. The activity of NADPH oxidase was increased mainly in glia-like cells in the hippocampal CA1 region after ischemia, and this increase was attenuated by HGF treatment. These results suggest that the protective effects of HGF against cerebral ischemia-induced cell death in the hippocampal CA1 region are related to the improvement of neuronal APE/Ref-1 expression and the inhibition of NADPH oxidase activity in glia-like cells.
Niimura
Makiko
M
Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Takagi
Norio
N
Takagi
Keiko
K
Mizutani
Reiko
R
Tanonaka
Kouichi
K
Funakoshi
Hiroshi
H
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Takeo
Satoshi
S
D017209:Apoptosis / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000473:pathology*; D019255:NADPH Oxidases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism
D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase