NEONATAL HI INJURY

Modulation of Triggering receptor expressed in myeloid cells 2 by gene transfer as novel neuroprotective estrategy for neonatal hypoxic ischemic brain injury using behavioural outcome as readout

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 Obiettivo del progetto (Objective)

'Insults during the perinatal stage of brain development lead to major causes of neurological disability throughout life, ranging from motor deficits, cognitive limitations, learning difficulties and even severe disabilities, such as cerebral palsy. In term newborn infants, hypoxic-ischemic (HI) brain injury is the most common cause of encephalopathy and seizures. Despite major improvements in neonatal care, there are no established therapeutic procedures successful for the prevention or treatment of perinatal brain lesions. In contrast to the adult, the immature brain displays distinct physiological and morphological features as a consequence of its ongoing postnatal development. Furthermore, experimental evidences also suggest that the inflammatory response associated to a CNS injury is exacerbated during immaturity. As brain development substantially influences the progression and hallmarks of brain injury, it is not possible to apply the results of medical research obtained in adults reliably to babies. The neonatal brain damage is poorly characterized, in this sense, studies performed in several laboratories have shown that the production of inflammatory molecules and inducers of oxidative stress by inflammatory cell types contribute to extension of neuronal damage and tissue injury induced by neurodegeneration. The field of endogenous regulatory receptors modulating inflammatory cell activation is largely unknown in the brain and no studies have yet focused on the damaged neonatal brain. In consequence, reaching a detailed knowledge of the endogenous inflammatory regulation the CNS during the early postnatal stage is essential for the proper development of neuroprotective therapies specific for this period. The modulation of TREM2 by gene transfer accompanied by the determination of the behavioural analysis will help to understand the mechanism regulating inflammatory response in neonatal injured brain and to reach a potential target for treatment.'

Introduzione (Teaser)

The pathophysiology of neonatal brain damage is poorly characterised. Using a mouse model, European researchers investigated the inflammatory events that lead to brain injury in infants.

Descrizione progetto (Article)

Approximately 60 000 infants are born every year with brain injury in the EU alone. Neonatal brain damage can occur as a result of hypoxic/ischaemic (HI) injury with potentially lifelong neurological disability and even severe disabilities, such as cerebral palsy. Hypothermia is a common treatment modality, which is effective only in moderate cases. There is an urgent need to develop therapeutic procedures for the prevention or treatment of perinatal brain lesions.

With this in mind, the EU-funded NEONATAL HI INJURY project set out to delineate the developmental processes that influence the outcome of brain injury. Major focus was given to the inflammatory responses associated with neonatal CNS injury and especially the role of endogenous regulatory receptors.

TREM2 is a receptor expressed on myeloid cells with an activating or suppressive function. Scientists found that TREM2 was expressed in microglia, the resident macrophages of the central nervous system, and its expression declined with development. TREM2 positive microglia co-expressed markers implicated in phagocytosis, strongly associating this receptor with brain inflammation and tissue damage.

To precisely evaluate the inflammatory events in the brain following ischemic injury, researchers performed carotid occlusion to induce hypoxia in neonatal mice. They observed extensive injury and inflammation, and performed detailed analysis at the cellular and molecular level. They identified a number of cytokines with altered expression after injury. Results indicate a potential role for STAT3, a transcription factor in regulating the balance between pro- and anti-inflammatory cytokines. Moreover, TREM2 expression increased during the 72 hours after hypoxic/ischemic injury, suggesting an upregulation of phagocytic activity of microglia as an intent to reduce inflammation. Functional relevance of its increased needs additional experiments.

Interestingly, when they looked at cognition and behaviour of injured animals, scientists discovered a gender bias which they aim to investigate further. Overall, the characterisation of the cellular responses in neonatal brain following injury will undoubtedly help in the design of improved therapies.