Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model

J Pineal Res. 2012 Sep;53(2):129-37. doi: 10.1111/j.1600-079X.2012.00978.x. Epub 2012 Feb 3.


Melatonin has beneficial effects against early brain injury (EBI) by modulating cerebral oxidative stress after experimental subarachnoid hemorrhage (SAH); however, few investigations relate to the precise underlying molecular mechanisms. To date, the relation between melatonin and nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) pathway has not been studied in SAH models. This study was undertaken to evaluate the influence of melatonin on Nrf2-ARE pathway in rats after SAH. Adult male SD rats were divided into four groups: (i) control group (n=18); (ii) SAH group (n=18); (iii) SAH+vehicle group (n=18); and (iv) SAH+melatonin group (n=18). The rat SAH model was induced by injection of 0.3mL fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20s. In SAH+melatonin group, melatonin was administered i.p. at 150mg/kg at 2 and 24hr after the induction of SAH. Brain samples were extracted at 48hr after SAH. Treatment with melatonin markedly increased the expressions of Nrf2-ARE pathway-related agents, such as Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutathione S-transferase α-1. Administration of melatonin following SAH significantly ameliorated EBI, including brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and neurological deficits. In conclusion, post-SAH melatonin administration may attenuate EBI in this SAH model, possibly through activating Nrf2-ARE pathway and modulating cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain Injuries / prevention & control*
  • Disease Models, Animal
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Male
  • Melatonin / therapeutic use*
  • NF-E2-Related Factor 2 / metabolism*
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Subarachnoid Hemorrhage / drug therapy*
  • Subarachnoid Hemorrhage / physiopathology


  • NF-E2-Related Factor 2
  • Melatonin