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  2. Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential

Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential

  • Int J Neuropsychopharmacol. 2014 Dec 30;18(6):pyu105. doi: 10.1093/ijnp/pyu105.
Eun-Joo Shin 1 Yoon Hee Chung 1 Hoang-Lan Thi Le 1 Ji Hoon Jeong 1 Duy-Khanh Dang 1 Yunsung Nam 1 Myung Bok Wie 1 Seung-Yeol Nah 1 Yo-Ichi Nabeshima 1 Toshitaka Nabeshima 1 Hyoung-Chun Kim 1
Affiliations

Affiliation

  • 1 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).
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.

Keywords

Klotho mutant mice; hippocampus; melatonin MT2 receptor/ERK/Nrf2; memory; oxidative stress.

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