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• W7706578 abstract "Neonatal brain injury resulting from cerebral hypoxia-ischemia (HI) is a major cause of mortality and long-term morbidity in the neonate. Unfortunately there is currently no pharmacological intervention to treat or stem HI-induced brain injury. Understanding how neurons are lost after neonatal HI is critical for the development of an intervention. Disruption to theserotonergic (5-HT) system early in life contributes to many adverse neurobehavioural and physiological changes in adults; many of which match those observed in the HI-affected neonate. The major hypotheses of this thesis were to determine the effects of HI on the serotonergic system in the neonatal brain and to investigate potential neuroinflammatory mechanisms underpinning damage to the 5-HT system in the neonatal brain following HI. These hypotheses were tested using a post-natal day 3 (P3) rat pup model of HI that involved occlusion of the right common carotid artery and subsequent exposure to 6% oxygen for 30 minutes at 37°C.The aim of the first experimental chapter (Chapter 2) of this thesis was to investigate the effects of P3 HI on the brain 5-HT system and the potential contribution of neuroinflammation to the HI-induced damage of the 5-HT network. Following P3 HI, parallel reductions in 5-HT transporter (SERT) expression, 5-HT levels in the brain and numbers of 5-HT-positive dorsal raphe neurons were observed one week after the P3 HI insult. Administration of a potent inhibitor of activated microglia, minocycline, attenuated HI-induced damage to the 5-HT system. Minocycline also prevented HI-induced increases in activated microglia and elevations in proinflammatory cytokines in the injured forebrain one week after insult. Therefore targeting P3 HI-induced neuroinflammation using minocycline could be a novel therapy to preserve the 5-HT system after neonatal HI.In Chapter 3 I investigated whether the decrease in brain 5-HT seen after P3 HI is a consequence of SERT translocating from the membrane to the cytosolic space in remaining neurons rendering it less effective at regulating 5-HT levels in the brain following neonatal HI. Another possibility is that nearby glial cells may possess SERT and contribute to the regulation of 5-HT in the synapse. However I demonstrate that in both non-injured and P3 HI-injured animals, SERT is retained on the cell membrane and is not harboured in the cytosol. Furthermore neuronal membrane SERT appears to be the primary regulator of synaptic 5-HT availability in the intact and P3 HIinjured neonatal brain as opposed to microglial cells or astrocytes since there was no evidence of SERT being located on either glial cell type.Further investigations revealed that damage to the serotonergic system was still evident 6 weeks after HI (Chapter 4). In addition, neuroinflammation was still evident in the brain 6 weeks after HI. Using the same minocycline treatment regimen (daily administration for 1 week post-HI) as that used in Chapter 2, it was found that minocycline treatment prevented long-term neuroinflammation as well as alleviating sustained damage to the 5-HT system. Thus short-term administration of minocycline may represent a long-term therapy to minimise 5-HT changes in the preterm brain following HI. The purpose of Chapter 5 was to investigate whether other neuroinflammatory mediators might contribute to the HI-induced damage of the 5-HT system in the neonatal brain. Elevated levels of proinflammatory cytokines and cyclooxygenase (COX) enzymes are evident in the brain after neonatal HI. I therefore investigated whether administration of ibuprofen, a non-steroidal antiinflammatory drug that inhibits COX enzymes and can lower proinflammatory cytokine levels, could alleviate damage to the 5-HT system after P3 HI. Post-HI administration of ibuprofen prevented disruption of the SERT, 5-HT neurons and 5-HT levels in the brain one week after P3 HI insult. Associated inhibition of HI-induced COX-2 expression, proinflammatory cytokine production and numbers of activated microglia suggests that inhibition of neuroinflammation using ibuprofen may be a promising intervention to ameliorate HI-induced damage to the 5-HT network.In summary, these series of studies are the first to reveal the immense damage and disruption that is incurred to the brain 5-HT system following neonatal HI. This thesis is also the first to demonstrate that neuroinflammation is the major mechanism responsible for HI-induced damage to the 5-HT system. I show that post-insult anti-inflammatory interventions are critical to stem on-going neuroinflammation and subsequent 5-HT network damage in the neonatal brain following HI. Therefore this thesis has contributed substantial knowledge to the mechanisms underpinning HI-induced brain injury and subsequent neuronal injury in the neonatal brain. This evidence will be beneficial for the implementation of pharmacological therapies to prevent the longterm neurobehavioural deficits that are incurred in those brain injured babies following neonatal HI." @default.
• W7706578 created "2016-06-24" @default.
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• W7706578 date "2012-12-01" @default.
• W7706578 modified "2023-09-27" @default.
• W7706578 title "Effects of hypoxia-ischemia on the serotonergic system in the neonatal brain" @default.
• W7706578 hasPublicationYear "2012" @default.
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