Neuroprotective effects of melatonin administered alone or in combination with topiramate in neonatal hypoxic-ischemic rat model

Restor Neurol Neurosci. 2012;30(5):435-44. doi: 10.3233/RNN-2012-120217.


Purpose: The objective of this study was to compare the effects of two neuroprotective agents; melatonin, a free radical scavenger and topiramate, AMPA/kainate receptor antagonist, administered alone or in combination in neonatal hypoxic-ischemic model.

Methods: After being anesthetized, 7-day-old pups underwent ischemia followed by exposure to hypoxia. The pups were divided into 4 groups in order to receive the vehicle, melatonin, topiramate and combination of topiramate and melatonin. These were administered intraperitoneally for three times; the first before ischemia, the second after hypoxia and the third 24 hours after the second dose. After sacrification, infarct volume and apoptosis were evaluated.

Results: Percent infarcted brain volume was significantly reduced in rats which received drugs compared with those which received the vehicle. The number of TUNEL positive cells per unit area in hippocampus and cortex were markedly reduced in drug treated groups compared with control group. No significant differences were found regarding percent infarcted brain volume and number of TUNEL positive cells among drug-treated groups.

Conclusions: Melatonin and topiramate, administered either alone or in combination significantly reduced the percent infarcted brain volume and number of TUNEL positive cells suggesting that these agents may confer benefit in treatment of infants with hypoxic-ischemic encephalopathy.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Brain Infarction / etiology
  • Brain Infarction / pathology
  • Brain Infarction / prevention & control
  • Caspase 3 / metabolism
  • Cell Count
  • Cell Death / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Fructose / administration & dosage
  • Fructose / analogs & derivatives*
  • Hypoxia-Ischemia, Brain / complications
  • Hypoxia-Ischemia, Brain / drug therapy*
  • Hypoxia-Ischemia, Brain / prevention & control*
  • In Situ Nick-End Labeling
  • Male
  • Melatonin / administration & dosage*
  • Neuroprotective Agents / administration & dosage*
  • Rats
  • Topiramate


  • Neuroprotective Agents
  • Topiramate
  • Fructose
  • Caspase 3
  • Melatonin