According to the World Health Organization (WHO), the perinatal period commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth. During this stage, the brain is highly vulnerable and may be subjected to several conditions that can affect normal neurological development, such as neonatal hypoxia-ischemia, neonatal asphyxia, placenta inflammation, brain trauma, metabolic diseases and genetic malformations. With an estimated incidence of 1.5 per 1000 live term newborns, hypoxic-ischemic encephalopathy (HIE) is the most frequent type of acquired neonatal brain injury. The manifestation of brain injury differs depending on the developmental status of the brain at the time of the insult (Rocha- Ferreira and Hristova, 2016). In pre-term infants (<37 completed weeks of gestation, according to WHO), white matter injury is predominant due to the maturation-dependent vulnerability of the oligodendrocyte (OL) lineage and to the presence of a relatively abundant developing oligodendrocyte progenitor cell (OPC) population, which is very vulnerable to excitotoxicity and neuroinflammation induced by hypoxia-ischemia. In contrast, in term babies, in which the maturation of the white matter is more advanced and the presence of oligodendrocyte progenitors is reduced, neuronal degeneration is the most commonly observed manifestation of injury. These conditions lead to long lasting sequelae, including seizures, cognitive and motor skills impairment, learning deficits and cerebral palsy. Despite the high level of infants affected every year by perinatal brain injuries and the severe long-term outcomes associated with these pathologies, therapies available for these patients are very limited. Therefore, there is a need to better understand the mechanisms underlying neurological disorders in infants to guide strategies that will prevent the injury and/or lead to functional recovery of the brain. This thesis aims to gain more insight on the mechanisms underlying neurodevelopment and neuroprotection after injury in the early postnatal brain. The dissertation is divided into two parts. The first part,entitled “The role of SIRT1 on the Beneficial Effects of Melatonin Administration Following Hypoxia-Ischemia Brain Injury”was carried out at the Department of Biomolecular Sciences, University of Urbino Carlo Bo. In this study, we used a model of hypoxia–ischemia in neonatal rats to address the mechanism underlying the neuroprotective effects of Melatonin, a naturally occurring neurohormone secreted by the pineal gland with antioxidant, anti-apoptotic and anti-inflammatory effects. In particular, we investigated the role of the silent information regulator 1 (SIRT1) in the early phase of the injury and the consequences of its modulation on autophagy. SIRT1 is a NAD-dependent deacetylase protein belonging to the class III of histone deacetylase family protein that play an important role in the signaling cascades activated during HIE, including cell death, inflammation, and oxidative stress. We found that Melatonin strongly and rapidly modulates SIRT1 activity indicating that SIRT1 modulation is an important player for its neuroprotective effect. The second part of this dissertation entitled “Elucidating the Functional Role of Endothelin-1 in the Developing Subventricular Zone” was carried out at the Center for Neuroscience Research, at Children’s National Medical Center, in Washington, DC. In this study, we analyzed the role of ET-1 in the OPC development in the developing postnatal subventricular zone (SVZ). In premature infants, hypoxic-ischemic damage is often associated with white matter brain injury (WMBI), characterized by loss of OLs and OPC differentiation failure (Back, 2017). The mechanisms regulating OPC proliferation and differentiation are still poorly understood but recent studies have identified Endothelin-1 (ET-1) as an endogenous peptide that may regulates their development. To study the role of ET-1 in this context, we used both organotypic brain slices and an in vivo mouse model of ET-1 overexpression. We found that ET-1 regulates OPC proliferation in the developing SVZ. In addition, we also characterized the expression pattern of ET-1 and its receptors in the piglet SVZ.
Perinatal Brain Injury: Mechanisms and Potential Pharmacological Therapies: The role of SIRT1 in the neuroprotective effect of melatonin and of endothelin-1 in oligodendrocyte progenitor cell development
Giulia RipariniConceptualization
;GALLO, VITTORIOSupervision
;Walter BalduiniSupervision
2018
Abstract
According to the World Health Organization (WHO), the perinatal period commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth. During this stage, the brain is highly vulnerable and may be subjected to several conditions that can affect normal neurological development, such as neonatal hypoxia-ischemia, neonatal asphyxia, placenta inflammation, brain trauma, metabolic diseases and genetic malformations. With an estimated incidence of 1.5 per 1000 live term newborns, hypoxic-ischemic encephalopathy (HIE) is the most frequent type of acquired neonatal brain injury. The manifestation of brain injury differs depending on the developmental status of the brain at the time of the insult (Rocha- Ferreira and Hristova, 2016). In pre-term infants (<37 completed weeks of gestation, according to WHO), white matter injury is predominant due to the maturation-dependent vulnerability of the oligodendrocyte (OL) lineage and to the presence of a relatively abundant developing oligodendrocyte progenitor cell (OPC) population, which is very vulnerable to excitotoxicity and neuroinflammation induced by hypoxia-ischemia. In contrast, in term babies, in which the maturation of the white matter is more advanced and the presence of oligodendrocyte progenitors is reduced, neuronal degeneration is the most commonly observed manifestation of injury. These conditions lead to long lasting sequelae, including seizures, cognitive and motor skills impairment, learning deficits and cerebral palsy. Despite the high level of infants affected every year by perinatal brain injuries and the severe long-term outcomes associated with these pathologies, therapies available for these patients are very limited. Therefore, there is a need to better understand the mechanisms underlying neurological disorders in infants to guide strategies that will prevent the injury and/or lead to functional recovery of the brain. This thesis aims to gain more insight on the mechanisms underlying neurodevelopment and neuroprotection after injury in the early postnatal brain. The dissertation is divided into two parts. The first part,entitled “The role of SIRT1 on the Beneficial Effects of Melatonin Administration Following Hypoxia-Ischemia Brain Injury”was carried out at the Department of Biomolecular Sciences, University of Urbino Carlo Bo. In this study, we used a model of hypoxia–ischemia in neonatal rats to address the mechanism underlying the neuroprotective effects of Melatonin, a naturally occurring neurohormone secreted by the pineal gland with antioxidant, anti-apoptotic and anti-inflammatory effects. In particular, we investigated the role of the silent information regulator 1 (SIRT1) in the early phase of the injury and the consequences of its modulation on autophagy. SIRT1 is a NAD-dependent deacetylase protein belonging to the class III of histone deacetylase family protein that play an important role in the signaling cascades activated during HIE, including cell death, inflammation, and oxidative stress. We found that Melatonin strongly and rapidly modulates SIRT1 activity indicating that SIRT1 modulation is an important player for its neuroprotective effect. The second part of this dissertation entitled “Elucidating the Functional Role of Endothelin-1 in the Developing Subventricular Zone” was carried out at the Center for Neuroscience Research, at Children’s National Medical Center, in Washington, DC. In this study, we analyzed the role of ET-1 in the OPC development in the developing postnatal subventricular zone (SVZ). In premature infants, hypoxic-ischemic damage is often associated with white matter brain injury (WMBI), characterized by loss of OLs and OPC differentiation failure (Back, 2017). The mechanisms regulating OPC proliferation and differentiation are still poorly understood but recent studies have identified Endothelin-1 (ET-1) as an endogenous peptide that may regulates their development. To study the role of ET-1 in this context, we used both organotypic brain slices and an in vivo mouse model of ET-1 overexpression. We found that ET-1 regulates OPC proliferation in the developing SVZ. In addition, we also characterized the expression pattern of ET-1 and its receptors in the piglet SVZ.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
