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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Behavior, Animal / drug effects*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glucuronidase / deficiency*
  • Glucuronidase / genetics
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Klotho Proteins
  • Melatonin / pharmacology*
  • Memory / drug effects*
  • Memory Disorders / enzymology
  • Memory Disorders / genetics
  • Memory Disorders / physiopathology
  • Memory Disorders / prevention & control*
  • Memory Disorders / psychology
  • Mice, Inbred C3H
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism*
  • Nootropic Agents / pharmacology*
  • Oxidative Stress / drug effects*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Receptor, Melatonin, MT2 / agonists*
  • Receptor, Melatonin, MT2 / antagonists & inhibitors
  • Receptor, Melatonin, MT2 / metabolism
  • Signal Transduction / drug effects*

Substances

  • Antioxidants
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Nootropic Agents
  • Protein Kinase Inhibitors
  • Receptor, Melatonin, MT2
  • Extracellular Signal-Regulated MAP Kinases
  • Glucuronidase
  • Klotho Proteins
  • Glutamate-Cysteine Ligase
  • Glutathione
  • Melatonin