title: Inhibition of apoptosis-inducing factor translocation is involved in protective effects of hepatocyte growth factor against excitotoxic cell death in cultured hippocampal neurons.
abstract: Although hepatocyte growth factor (HGF) and its receptor are expressed in various regions of the brain, their effects and mechanism of action under pathological conditions remain to be determined. Over-activation of the N-methyl-d-aspartate (NMDA) receptor, an ionotropic glutamate receptor, has been implicated in a variety of neurological and neurodegenerative disorders. We investigated the effects of HGF on the NMDA-induced cell death in cultured hippocampal neurons and sought to explore their mechanisms. NMDA-induced cell death and increase in the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells were prevented by HGF treatment. Although neither the total amounts nor the mitochondrial localization of Bax, Bcl-2 and Bcl-xL were affected, caspase 3 activity was increased after NMDA exposure. Treatment with HGF partially prevented this NMDA-induced activation of caspase 3. Although the amount of apoptosis-inducing factor (AIF) was not altered, translocation of AIF into the nucleus was detected after NMDA exposure. This NMDA-induced AIF translocation was reduced by treatment with HGF. In addition, increased poly(ADP-ribose) polymer formation after NMDA exposure was attenuated by treatment with HGF. These results suggest that the protective effects of HGF against NMDA-induced neurotoxicity are mediated via the partial prevention of caspase 3 activity and the inhibition of AIF translocation to the nucleus.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ishihara
authors.forename: Norio
authors.initials: N
authors.lastname: Takagi
authors.forename: Makiko
authors.initials: M
authors.lastname: Niimura
authors.forename: Keiko
authors.initials: K
authors.lastname: Takagi
authors.forename: Midori
authors.initials: M
authors.lastname: Nakano
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tanonaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Funakoshi
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeo
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage*; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011247:Pregnancy; D021381:Protein Transport / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D009498:Neurotoxins; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D011064:Poly Adenosine Diphosphate Ribose; D016202:N-Methylaspartate; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D010751:Phosphopyruvate Hydratase