title: Role of heme oxygenase-1 protein in the neuroprotective effects of cyclopentenone prostaglandin derivatives under oxidative stress.
abstract: Previously we found that some cyclopenteone prostaglandin derivatives (PGs), referred to as neurite outgrowth-promoting PGs (NEPPs), have dual biological activities of promoting neurite outgrowth and preventing neuronal death [Satoh et al. (2000) J. Neurochem., 75, 1092-1102; Satoh et al. (2001) J. Neurochem., 77, 50-62; Satoh et al. (2002) In Kikuchi, II. (ed.), Strategenic Medical Science Against Brain Attack. Springer-Verlag, Tokyo, pp. 78-93]. To investigate possible cellular mechanisms of the neuroprotective effects, we performed oligo hybridization-based DNA array analysis with mRNA isolated from HT22, a cell line that originated from a mouse hippocampal neuron. Several transcripts up-regulated by NEPP11 were identified. Because heme oxygenase 1 (HO-1) mRNA was the most prominently induced and was earlier reported to protect neuronal and non-neuronal cells against oxidative stress, we focused on it as a possible candidate responsible for the neuroprotective effects. We found NEPP11 to induce HO-1 protein (32 kDa) in HT22 cells in both the presence and the absence of glutamate, whereas non-neuroprotective prostaglandins (PGs) Delta12-PGJ2 or PGA2 did not. Overexpression of HO-1-green fluorescence protein (GFP) fusion protein significantly protected HT22 cells against oxidative glutamate toxicity, whereas that of GFP alone did not. Furthermore, biliverdin and bilirubin, products of HO-1 enzymatic activity on heme, protected HT22 cells from oxidative glutamate toxicity. These results, together with our previous results, suggest that NEPP11 activates the expression of HO-1 and that HO-1 produces biliverdin and bilirubin, which result in the inhibition of neuronal death induced by oxidative stress. NEPP11 is the first molecular probe reported to have a neuroprotective action through induction of HO-1 in neuronal cells.
authors.affiliation: Department of Welfare Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate 020-8551, Japan. tsatoh@iwate-u.ac.jp
authors.forename: Takumi
authors.initials: T
authors.lastname: Satoh
authors.forename: Megumi
authors.initials: M
authors.lastname: Baba
authors.forename: Daisaku
authors.initials: D
authors.lastname: Nakatsuka
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Kyoji
authors.initials: K
authors.lastname: Furuta
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatanaka
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001663:Bilirubin / Q000502:physiology; D001664:Biliverdine / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000378:metabolism; D018846:Excitatory Amino Acids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology*; D051547:Heme Oxygenase-1; D008164:Luminescent Proteins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011453:Prostaglandins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D011454:Prostaglandins A / Q000819:agonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D018846:Excitatory Amino Acids; D008164:Luminescent Proteins; D008565:Membrane Proteins; C424427:NEPP11 compound; C424426:NEPP6 compound; D018696:Neuroprotective Agents; D011453:Prostaglandins; D011454:Prostaglandins A; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; C037112:9-deoxy-delta-9-prostaglandin D2; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C100008:prostaglandin A2; D001664:Biliverdine; C013905:cyclopentenone; D001663:Bilirubin; D015230:Prostaglandin D2