Rapid modulation of the silent information regulator 1 by melatonin after hypoxia‐ischemia in the neonatal rat brain

Abstract

Increasing evidence indicates that melatonin possesses protective effects toward different kinds of damage in various organs, including the brain. In a neonatal model of hypoxia-ischemia (HI), melatonin was neuroprotective and preserved the expression of the silent information regulator 1 (SIRT1) 24 hours after the insult. This study aimed to gain more insight into the role of SIRT1 in the protective effect of melatonin after HI by studying the early (1 hour) modulation of SIRT1 and its downstream targets, and the consequences on necrosis, apoptosis, autophagy, and glial cell activation. We found that melatonin administered 5 minutes after the ischemic insult significantly reduced necrotic cell death assessed 1 hour after its administration. In parallel, we found a reduced activation of the early phases of intrinsic apoptosis, detected by reduced BAX translocation to the mitochondria and preservation of the mitochondrial expression of cytochrome C, indicating a reduced outer mitochondrial membrane permeabilization in the melatonin-treated ischemic animals. These effects were concomitant to increased expression and activity of SIRT1, reduced expression and acetylation of p53, and increased autophagy activation. Melatonin also reduced HI-induced glial cells activation. SIRT1 was expressed in neurons after HI and melatonin but not in reactive glial cells expressing GFAP. Colocalization between SIRT1 and GFAP was found in some cells in control conditions. In summary, our results provide more insight into the connection between SIRT1 and melatonin in neuroprotection. The possibility that melatonin-induced SIRT1 activity might contribute to differentiate neuronal progenitor cells during the neurodegenerative process needs to be further investigated.

Melatonin Acts in Synergy with Hypothermia to Reduce Oxygen-Glucose Deprivation-Induced Cell Death in Rat Hippocampus Organotypic Slice Cultures

“…Melatonin, on the other hand, reduced injury in organotypic hippocampal slice cultures in normothermic conditions (37 ° C) in a concentration-dependent manner, with a maximal neuroprotection at 100 μΜ. These data are in agreement with previous findings in the same model [26], as well as in in vivo models of brain injury [14]. Using concentrations of melatonin showing a submaximal neuroprotective effect (25 and 50 μM) in combination with 6 h of hypothermia, we found that cell survival was comparable to the control condition not subjected to OGD, indicating a synergy of the combination of the hormone with hypothermia.…”

“…Melatonin is a potent scavenger of reactive oxygen species with anti-inflammatory effects in conditions associated with oxidative stress as well as immunomodulatory effects in the presence of an exacerbated immune response [11,12]. When given before or immediately after hypoxia-ischemia in different models of perinatal brain injury, melatonin showed neuroprotective effects [13][14][15]. Melatonin also appeared effective in different neonatal pathological conditions, including neonatal sepsis, bronchopulmonary dysplasia, and neonatal asphyxia [16,17].…”

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia

“…Currently, the length of melatonin treatment in HIE for optimal neuroprotection is unknown. Preclinical studies are necessary because new evidence shows that melatonin can enhance cell and tissue regeneration and is protective during acute neurodegeneration . The injured immature brain holds high‐level neural plasticity and could be particularly susceptible to treatment modalities such as melatonin that can trigger neuron generation (reactive neurogenesis) and creation of new neural networks.…”

Elevation of autophagy rescues spermatogenesis by inhibiting apoptosis of mouse spermatocytes

“…These results indicate that autophagy inhibition by hypoxia plays an important role in hypoxia-induced GC-2 cell apoptosis, which is supported by published studies in non-germ cells under ischemic hypoxia conditions. Melatonin (an agonist of autophagy) administered 5 min after an ischemic insult can significantly reduce activation of intrinsic apoptosis (Carloni et al 2017). Induction of autophagy is accompanied by reduced cardiomyocyte apoptotic rate and decreased expression levels of BAX/BCL-2 and active caspase in the border zone of 3-day-infarcted mice following high-mobility group box-1 (HMGBI, an agonist of autophagy) treatment (Foglio et al 2017).…”