Pre- and post-natal melatonin administration partially regulates brain oxidative stress but does not improve cognitive or histological alterations in the Ts65Dn mouse model of Down syndrome

Behav Brain Res. 2017 Sep 15;334:142-154. doi: 10.1016/j.bbr.2017.07.022. Epub 2017 Jul 23.


Melatonin administered during adulthood induces beneficial effects on cognition and neuroprotection in the Ts65Dn (TS) mouse model of Down syndrome. Here, we investigated the effects of pre- and post-natal melatonin treatment on behavioral and cognitive abnormalities and on several neuromorphological alterations (hypocellularity, neurogenesis impairment and increased oxidative stress) that appear during the early developmental stages in TS mice. Pregnant TS females were orally treated with melatonin or vehicle from the time of conception until the weaning of the offspring, and the pups continued to receive the treatment from weaning until the age of 5 months. Melatonin administered during the pre- and post-natal periods did not improve the cognitive impairment of TS mice as measured by the Morris Water maze or fear conditioning tests. Histological alterations, such as decreased proliferation (Ki67+ cells) and hippocampal hypocellularity (DAPI+ cells), which are typical in TS mice, were not prevented by melatonin. However, melatonin partially regulated brain oxidative stress by modulating the activity of the primary antioxidant enzymes (superoxide dismutase in the cortex and catalase in the cortex and hippocampus) and slightly decreasing the levels of lipid peroxidation in the hippocampus of TS mice. These results show the inability of melatonin to prevent cognitive impairment in TS mice when it is administered at pre- and post-natal stages. Additionally, our findings suggest that to induce pro-cognitive effects in TS mice during the early stages of development, in addition to attenuating oxidative stress, therapies should aim to improve other altered processes, such as hippocampal neurogenesis and/or hypocellularity.

Keywords: Down syndrome; Melatonin; Memory; Neurogenesis; Oxidative stress; Ts65Dn.

MeSH terms

  • Animals
  • Animals, Newborn
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Catalase / metabolism
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Cognition / drug effects*
  • Cognition / physiology
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Disease Models, Animal
  • Down Syndrome / drug therapy*
  • Down Syndrome / metabolism
  • Down Syndrome / pathology
  • Fear / drug effects
  • Fear / physiology
  • Ki-67 Antigen / metabolism
  • Lipid Peroxidation / drug effects
  • Lipid Peroxidation / physiology
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Melatonin / administration & dosage*
  • Melatonin / blood
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neuroprotective Agents / administration & dosage*
  • Neuroprotective Agents / blood
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Random Allocation
  • Superoxide Dismutase / metabolism


  • Ki-67 Antigen
  • Neuroprotective Agents
  • Catalase
  • Superoxide Dismutase
  • Melatonin