title: Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential.
abstract: BACKGROUND
  We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment.
  
  
  METHODS
  First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin.
  
  
  RESULTS
  Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice.
  
  
  CONCLUSIONS
  Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential.
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Hoang-Lan Thi
authors.initials: HL
authors.lastname: Le
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Duy-Khanh
authors.initials: DK
authors.lastname: Dang
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Yunsung
authors.initials: Y
authors.lastname: Nam
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Myung Bok
authors.initials: MB
authors.lastname: Wie
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Nah
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Yo-Ichi
authors.initials: Y
authors.lastname: Nabeshima
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000090265:Klotho Proteins; D008550:Melatonin / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018697:Nootropic Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044123:Receptor, Melatonin, MT2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D018697:Nootropic Agents; D047428:Protein Kinase Inhibitors; D044123:Receptor, Melatonin, MT2; D048049:Extracellular Signal-Regulated MAP Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D008550:Melatonin
keywords: Klotho mutant mice; hippocampus; melatonin MT2 receptor/ERK/Nrf2; memory; oxidative stress