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

Eun Joo Shin, Yoon Hee Chung, Hoang Lan Thi Le, Ji Hoon Jeong, Duy Khanh Dang, Yunsung Nam, Myung Bok Wie, Seung Yeol Nah, Yo Ichi Nabeshima, Toshitaka Nabeshima, Hyoung Chun Kim

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)


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 melatoninmediated 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.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalInternational Journal of Neuropsychopharmacology
Issue number6
Publication statusPublished - 01-01-2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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