The use of melatonin in hypoxic-ischemic brain damage: an experimental study

Balduini, Walter; Carloni, Silvia; Perrone, Serafina; Bertrando, Sara; Tataranno, Maria Luisa; Negro, Simona; Proietti, Fabrizio; Longini, Mariangela; Buonocore, Giuseppe

doi:10.3109/14767058.2012.663232

Cited by 70 publications

(73 citation statements)

References 23 publications

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“…Further studies would be valuable to assess whether these morphologic changes were associated with altered microglial toxicity; however, this outcome is highly consistent with previous reports of reduced microglial activation by melatonin in rodents and fetal sheep after hypoxiaischemia. 5,11,12 It is likely that these effects were related to suppression of the neural microglia. Maternal melatonin was associated with a reduced peripheral white cell response but its effects were not significantly different from ethanol.…”

Section: Discussionmentioning

confidence: 99%

Partial Neural Protection with Prophylactic Low-Dose Melatonin after Asphyxia in Preterm Fetal Sheep

Drury

Davidson

Bennet

et al. 2013

J Cereb Blood Flow Metab

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Melatonin is a naturally occurring indolamine with mild antioxidant properties that is neuroprotective in perinatal animals. There is limited information on its effects on preterm brain injury. In this study, 23 chronically instrumented fetal sheep received 25 minutes of complete umbilical cord occlusion at 101 to 104 days gestation (term is 147 days). Melatonin was administered to the ewe 15 minutes before occlusion (0.1 mg/kg bolus followed by 0.1 mg/kg per hour for 6 hours, n ¼ 8), or the equivalent volume of vehicle (2% ethanol, n ¼ 7), or saline (n ¼ 8), or maternal saline plus sham occlusion (n ¼ 8). Sheep were killed after 7 days recovery in utero. Fetal blood pressure, heart rate, nuchal activity, and temperature were similar between groups. Vehicle infusion was associated with improved neuronal survival in the caudate nucleus, but greater neuronal loss in the regions of the hippocampus, with reduced proliferation and increased ameboid microglia in the white matter (Po0.05). Maternal melatonin infusion was associated with faster recovery of fetal EEG, prolonged reduction in carotid blood flow, similar neuronal survival to vehicle, improved numbers of mature oligodendrocytes, and reduced microglial activation in the white matter (Po0.05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin. Keywords: asphyxia; brain; ethanol; melatonin; neuroprotection; preterm fetus INTRODUCTION Birth asphyxia is relatively common with preterm birth, and remains a significant cause of neonatal death and neurodevelopmental delay. 1 Excess free radical production during asphyxia and early reperfusion are associated with lipid peroxidation, nucleic acid damage, and mitochondrial dysfunction that promote cell death. 2 Melatonin is a naturally occurring indolamine involved in circadian rhythm, which also has antioxidant properties. 3,4 It readily crosses the human and ovine placentae making it an attractive option for prophylactic treatment of fetuses at high risk of perinatal hypoxia. 4 Melatonin given before and immediately after hypoxia-ischemia is neuroprotective in postnatal rodents. [5][6][7][8][9] Postnatally, high-dose (5 mg/kg per hour over 6 hours) melatonin given immediately after hypoxia-ischemia in term piglets augmented protection from therapeutic hypothermia on both magnetic resonance spectroscopy markers of anaerobic stress, and histopathology. 10 In contrast, there have been few studies of antenatal treatment and relatively limited large-animal evidence that prophylactic lowdose melatonin can protect against hypoxic-ischemic injury in the preterm fetus. In fetal sheep, Miller et al 11 showed that maternal prophylactic melatonin (1 mg total) given before 10-minute umbilical cord occlusion at term-equivalent was associated with reduced brain lipid peroxidation, neuronal death, microglial activation, and astrogliosis. 11,12 In preterm fetal sheep at 0.6 gestation (Term ¼ 147 days) fetal infusion of high-dose (20 mg/kg) J...

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Section: Discussionmentioning

confidence: 99%

Partial Neural Protection with Prophylactic Low-Dose Melatonin after Asphyxia in Preterm Fetal Sheep

Drury

Davidson

Bennet

et al. 2013

J Cereb Blood Flow Metab

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“…Numerous experimental in vivo studies evidenced that doses in a range of 5–15 mg/kg of melatonin, mainly administered intraperitoneally, exert neuroprotective effects in the ischemic cascade at several critical points (Guerrero et al, 1997; Pei et al, 2003; Pei and Cheung, 2004; Chen H. Y. et al, 2006; Carloni et al, 2008; Signorini et al, 2009; Balduini et al, 2012; Alonso-Alconada et al, 2013; Paredes et al, 2015). …”

Section: Melatoninmentioning

confidence: 99%

Melatonin and Nitrones As Potential Therapeutic Agents for Stroke

Romero

Ramos

Patiño

et al. 2016

Front. Aging Neurosci.

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Stroke is a disease of aging affecting millions of people worldwide, and recombinant tissue-type plasminogen activator (r-tPA) is the only treatment approved. However, r-tPA has a low therapeutic window and secondary effects which limit its beneficial outcome, urging thus the search for new more efficient therapies. Among them, neuroprotection based on melatonin or nitrones, as free radical traps, have arisen as drug candidates due to their strong antioxidant power. In this Perspective article, an update on the specific results of the melatonin and several new nitrones are presented.

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“…Melatonin, the main secretory product of the pineal gland, is known for its neuroprotective effect mainly through its FRs scavenging and antioxidant properties. It can readily cross the blood--brain barrier and effectively prevent neuronal loss in experimental models of ischemia [76]. Melatonin may alter the activities of detoxifying enzymes, thereby improving the total antioxidant defense capacity of the cells.…”

Section: Resultsmentioning

confidence: 99%