Melatonin ameliorates cognitive impairment induced by sleep deprivation in rats: role of oxidative stress, BDNF and CaMKII

Behav Brain Res. 2013 Nov 1;256:72-81. doi: 10.1016/j.bbr.2013.07.051. Epub 2013 Aug 6.


Sleep deprivation (SD) has been shown to induce oxidative stress which causes cognitive impairment. Melatonin, an endogenous potent antioxidant, protects neurons from oxidative stress in many disease models. The present study investigated the effect of melatonin against SD-induced cognitive impairment and attempted to define the possible mechanisms involved. SD was induced in rats using modified multiple platform model. Melatonin (15 mg/kg) was administered to the rats via intraperitoneal injection. The open field test and Morris water maze were used to evaluate cognitive ability. The cerebral cortex (CC) and hippocampus were dissected and homogenized. Nitric oxide (NO) and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) enzyme activity of hippocampal and cortical tissues (10% wet weight per volume) were performed to determine the level of oxidative stress. The expression of brain-derived neurotrophic factor (BDNF) and calcium-calmodulin dependent kinase II (CaMKII) proteins in CC and hippocampus was assayed by means of immunohistochemistry. The results revealed that SD impairs cognitive ability, while melatonin treatment prevented these changes. In addition, melatonin reversed SD-induced changes in NO, MDA and SOD in both of the CC and hippocampus. The results of immunoreactivity showed that SD decreased gray values of BDNF and CaMKII in CC and hippocamal CA1, CA3 and dentate gyrus regions, whereas melatonin improved the gray values. In conclusion, our results suggest that melatonin prevents cognitive impairment induced by SD. The possible mechanism may be attributed to its ability to reduce oxidative stress and increase the levels of CaMKII and BDNF in CC and hippocampus.

Keywords: BDNF; CC; CG; CaMKII; Calcium-calmodulin dependent kinase II; Cognitive impairment; DG; DTC; EL; FMT; ITT; LTP; MDA; MSD(1); MSD(2); Melatonin; NCP; NO; OF; Oxidative stress; P-CaMKII; PBS; REM; ROS; SD; SD(1); SD(2); SOD; Sleep deprivation; TMD; WPG(1); WPG(2); brain-derived neurotrophic factor; cerebral cortex; control group; dentate gyrus; distance to the center; escape latency; faster movement time; inner toriod time; long-term potentiation; malondialdehyde; melatonin with sleep deprivation 2; melatonin with sleep deprivation group 1; nitric oxide; number of crossings over the former platform location; open field; phosphate buffer saline; phosphorylated Calcium-calmodulin dependent kinase II; rapid eye movent; reactive oxygen species; sleep deprivation; sleep deprivation 2; sleep deprivation group 1; superoxide dismutase; total movement distance; wide platform group 1; wide platform group 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Brain / drug effects*
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology*
  • Cognition Disorders / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Immunohistochemistry
  • Male
  • Malondialdehyde / metabolism
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Melatonin / pharmacology*
  • Nitric Oxide / metabolism
  • Nootropic Agents / pharmacology*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Rats, Sprague-Dawley
  • Sleep Deprivation / complications*
  • Superoxide Dismutase / metabolism


  • Antioxidants
  • Brain-Derived Neurotrophic Factor
  • Nootropic Agents
  • Nitric Oxide
  • Malondialdehyde
  • Superoxide Dismutase
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Melatonin