Brain damage in preterm newborns and maternal medication: the ELGAN Study.

OBJECTIVE: We sought to evaluate the association between maternal medication use during pregnancy and cerebral white matter damage and cerebral palsy (CP) among very preterm infants. STUDY DESIGN: This analysis of data from the Extremely Low Gestational Age Newborns (ELGAN) Study included 877 infants born <28 weeks' gestation. Mothers were interviewed, charts were reviewed, placentas were cultured and assessed histologically, and children were evaluated at 24 months corrected age. A diagnostic algorithm classified neurologic findings as quadriparetic CP, diparetic CP, hemiparetic CP, or no CP. RESULTS: After adjustment for the potential confounding of disorders for which medications might have been indicated, the risk of quadriparetic CP remained elevated among the infants of mothers who consumed aspirin (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.3-6.9) and nonsteroidal antiinflammatory drugs (NSAIDs) (OR, 2.4; 95% CI, 1.04-5.8). The risk of diparetic CP was also associated with maternal consumption of an NSAID, but only if the consumption was not approved by a physician (OR, 3.5; 95% CI 1.1-11.0). CONCLUSION: The possibility that aspirin and NSAID use in pregnancy could lead to perinatal brain damage cannot be excluded.

Role of p75NTR in NMDAR-mediated excitotoxic brain injury in neonatal mice.

BACKGROUND: Perinatal brain injury in preterm infants is a major cause of neurological handicap. The role of the neurotrophin receptor p75 (p75(NTR)) in the pathogenesis and repair of neonatal excitotoxic brain injury is unknown. Depending on a complex interplay of neurotrophin signalling, p75(NTR) can, in addition to its trophic function, also induce apoptosis. HYPOTHESIS: We hypothesised that excitotoxicity increases p75(NTR) expression and p75(NTR) knockout (KO) mice have a significantly smaller lesion size upon excitotoxicity as compared to wild-type (WT) mice. METHODS: We used an established animal model of neonatal excitotoxic brain injury mimicking several key aspects of human preterm brain damage. We subjected five-day-old WT and KO mice to excitotoxic injury by means of a single intracranial ibotenate injection (N-methyl-D-aspartate receptor agonist, NMDAR) into one brain hemisphere. Lesion size, number of activated caspase-3- and apoptosis-inducing factor (AIF)-positive cells were determined as outcome parameters. Gender analyses were taken into account retrospectively. RESULTS: NMDAR-mediated excitotoxicity induced an upregulation of p75(NTR) expression in the peri-lesion area. Lesion size was significantly increased in female KO as compared to male KO animals. Knockout of p75(NTR) reduced the number of activated caspase-3 but not AIF-positive cells after NMDAR-mediated excitotoxic injury independently of gender. CONCLUSION: Since NMDAR-mediated excitotoxic brain injury induced p75(NTR) expression and caspase-3-activated apoptosis in p75(NTR) KO animals was decreased, we conclude that activation of p75(NTR) contributes to NMDAR-mediated apoptosis in the neonatal brain. An increase in lesion size in female animals after excitotoxic brain injury suggests that in females p75(NTR) seems to play a dual role.

Absence of striatal newborn neurons with mature phenotype following defined striatal and cortical excitotoxic brain injuries.

Experimental stroke and excitotoxic brain lesion to the striatum increase the proliferation of cells residing within the ventricular wall and cause subsequent migration of newborn neuroblasts into the lesioned brain parenchyma. In this study, we clarify the different events of neurogenesis following striatal or cortical excitotoxic brain lesions in adult rats. Newborn cells were labeled by intraperitoneal injection of bromo-deoxy-uridine (BrdU), or by green fluorescent protein (GFP)-expressing lentiviral vectors injected into the subventricular zone (SVZ). We show that only neural progenitors born the first 5 days in the SVZ reside and expand within this neurogenic niche over time, and that these early labeled cells are more prone to migrate towards the striatum as neuroblasts. However, these neuroblasts could not mature into NeuN+ neurons in the striatum. Furthermore, we found that cortical lesions, close or distant from the SVZ, could not upregulate SVZ cell proliferation nor promote neurogenesis. Our study demonstrates that both the time window for labeling proliferating cells and the site of lesion are crucial when assessing neurogenesis following brain injury.

Supporting the long-term residential care needs of older homeless people with severe alcohol-related brain injury in Australia: the Wicking Project.

For years, community service providers have been frustrated with the lack in availability of long-term, specialized supported accommodation for older people, particularly older homeless people, with severe acquired brain injury (ABI) and challenging behaviors. Although the incidence of ABI (particularly alcohol-related brain injury) is far wider than being confined to the homeless population, it is frequently misdiagnosed and very often misunderstood Wintringham is an independent welfare company in Melbourne, Australia, that provides secure, affordable, long-term accommodation and high quality services to older homeless people. The high incidence of alcohol abuse among the resident population has led us to adapt our model ofcare to accommodate a complexity of need. However, there are some individuals with severely affected behaviors that continue to challenge Wintringham's capacity to provide adequate support. The deficiency in highly specialized, long-term supported accommodation for older people with severe alcohol-related brain injury (ARBI) is the driving force behind this project. We aim to further develop and improve the current Wintringham model of residential care to better support people with these complex care needs. We will report on the synthesis of this project which aims to test a specialized model that can be reproduced or adapted by other service providers to improve the life circumstances of these frequently forgotten people.

Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity.

The catalytic subunit of telomerase reverse transcriptase (TERT) protects dividing cells from replicative senescence in vitro. Here, we show that expression of TERT mRNA is induced in the ipsilateral cortical neurons after occlusion of the middle cerebral artery in adult mice. Transgenic mice that overexpress TERT showed significant resistance to ischemic brain injury. Among excitotoxicity, oxidative stress, and apoptosis comprising of routes of ischemic neuronal death, NMDA receptor-mediated excitotoxicity was reduced in forebrain cell cultures overexpressing TERT. NMDA-induced accumulation of cytosolic free Ca2+ ([Ca2+]c) was reduced in forebrain neurons from TERT transgenic mice, which was attributable to the rapid flow of [Ca2+]c into the mitochondria from the cytosol without change in Ca2+ influx and efflux through the plasma membrane. The present study provides evidence that TERT is inducible in postmitotic neurons after ischemic brain injury and prevents NMDA neurotoxicity through shift of the cytosolic free Ca2+ into the mitochondria, and thus plays a protective role in ameliorating ischemic neuronal cell death.