Background: Perinatal hypoxia-ischemia is a major cause of mortality and long-term neurological deficits. Objectives: The objective of this study was to compare the effects of two neuroprotective agents; magnesium sulfate and melatonin, administered alone or in combination, on brain infarct volume and TUNEL positivity in a neonatal hypoxic-ischemic (HI) rat model. Methods: After being anesthetized, 7-day-old pups (n = 80) underwent ischemia followed by exposure to hypoxia for 2 h. The pups were then divided equally and randomly into 4 groups in order to receive the vehicle (saline, control group), magnesium sulfate, melatonin or a combination of magnesium sulfate and melatonin. Treatments were administered intraperitoneally three times; the first being just before ischemia, the second after hypoxia and the third 24 h after the second dose. The pups were sacrificed on postnatal day 10, their brains harvested and evaluated for infarct volume and neuronal apoptosis. Results: Percent infarcted brain volume was significantly reduced in pups receiving the drugs (either magnesium sulfate, melatonin or their combination) compared with those receiving the vehicle. In addition, TUNEL staining showed markedly reduced numbers of TUNEL-positive cells per unit area in the CA1, CA3 and dentate gyrus regions of the hippocampus and in the cortex. However, no statistically significant differences were found regarding percent infarcted brain volume and number of TUNEL-positive cells among the drug-treated groups. Conclusions: Magnesium sulfate and melatonin, two agents acting at different stages of HI brain damage, administered either alone or in combination, significantly reduced the percent infarcted brain volume and TUNEL positivity, suggesting that these agents may confer a possible benefit in the treatment of infants with HI encephalopathy.

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Although accumulating evidence suggests that increased extracellular glutamate concentrations may play an important role in hypoxic-ischemic brain injury, dopamine and other catecholamines also seem to be involved. The N-methyl-D-aspartate receptor antagonist MK 801 and moderate hypothermia (32-34 degrees C) are each known to be neuroprotective, but their combined effect on the release and metabolism of neurotransmitters is unknown. Seven-day-old pups (n: 150) underwent right common carotid artery ligation to induce hemispheric ischemia, and were later subjected to 120 minutes of hypoxia with 8% O2 and 92% N2O. Half the rats (Group I, n: 74) were subjected to normothermic conditions throughout the hypoxic period. Moderate hypothermia (30-32 degrees C) was induced in the other pups (Group II, n: 76) immediately after artery occlusion, and was maintained throughout the hypoxic period. Prior to inducing hypoxia, half of the rats in each group (Groups IA and IIA) received vehicle solution (0.9% NaCI) and the other rats (Groups IB and IIB) received MK 801 (0.5 mg/kg) subcutaneously at 45 and 120 minutes after occlusion. Intracerebral temperature was recorded every 15 minutes after occlusion. Infarct area (n: 40) was calculated after staining with 2% 2,3,5 triphenyltetrazolium chloride. Neuronal damage (n: 42) was assessed by quantifying CA1-CA3 neuronal loss at five hippocampal levels. The amount of damage to the monoamine system of the corpus striatum was determined based on the dopamine and 3,4 dihydroxyphenylacetic acid levels in the corpus striatum in both hemispheres (n: 46), as measured by high-pressure liquid chromatography and compared with normal control pups' values (n: 10). The normothermia/saline-treated pups had significantly larger infarct areas than the MK 801 only, hypothermia only, or MK 801/hypothermia combination groups. Neuropathological examination and striatal tissue monoamine data also confirmed marked neuronal damage in this group. Although MK 801 treatment alone resulted in significantly smaller infarct area and less tissue damage than was observed in the normothermia/saline-treated group, the moderate hypothermia and the MK 801/hypothermia combination treatment groups both exhibited better neuronal protection, especially in the corpus striatum. The rats that received combined treatment also had a significantly lower mortality rate.

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.