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Neonatal encephalopathy: Pre-clinical studies in neuroprotection. Vannucci, R. C. & Vannucci, S. J. Perinatal hypoxic-ischemic brain damage: Evolution of an animal model. Rodent neonatal bilateral carotid artery occlusion with hypoxia mimics human hypoxic-ischemic injury. Quinn, R. Comparing rat’s to human’s age: How old is my rat in people years?. Vannucci, R. C. Experimental models of perinatal hypoxic-ischemic brain damage. Rat model of perinatal hypoxic-ischemic brain damage. Hypoxic preconditioning suppresses glial activation and neuroinflammation in neonatal brain insults. Kreutzberg, G. W. Microglia: A sensor for pathological events in the CNS. Brain inflammation and adult neurogenesis: The dual role of microglia.

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Sildenafil improves functional and structural outcome of retinal injury following term neonatal hypoxia-ischemia. Sildenafil mediates blood-flow redistribution and neuroprotection after neonatal hypoxia-ischemia. Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis. Phosphodiesterase 5 inhibition at disease onset prevents experimental autoimmune encephalomyelitis progression through immunoregulatory and neuroprotective actions. Sildenafil (Viagra) protective effects on neuroinflammation: The role of iNOS/NO system in an inflammatory demyelination model.

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Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice. Sildenafil enhances neurogenesis and canada sildenafil oligodendrogenesis in ischemic brain of middle-aged mouse. & Peixoto, C. A. Sildenafil (Viagra®) down regulates cytokines and prevents demyelination in a cuprizone-induced MS mouse model. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Ciliary neurotrophic factor and interleukin-6 differentially activate microglia. Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina. & Hasanein, B. M. IL-1beta, IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy. & Feng, Z. C.

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Increased umbilical cord plasma interleukin-1 beta levels was correlated with adverse outcomes of neonatal hypoxic-ischemic encephalopathy.

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The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. Brief update on animal models of hypoxic-ischemic encephalopathy and neonatal stroke. The influence of immaturity on hypoxic-ischemic brain damage in the rat. & Vannucci, S. J. Silveira, R. C. & Procianoy, R. S. Interleukin-6 and tumor necrosis factor-alpha levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic-ischemic encephalopathy.

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Mallard, C., Tremblay, M. E. & Vexler, Z. S. Microglia and neonatal brain injury.

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Douglas-Escobar, M. & Weiss, M. D. Hypoxic-ischemic encephalopathy: A review for the clinician. Bednar, M.

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M. The role of sildenafil in the treatment of stroke. Functional recovery in aged and young rats after embolic stroke: Treatment with a phosphodiesterase type 5 inhibitor. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. Sildenafil improves brain injury recovery following term neonatal hypoxia-ischemia in male rat pups. Enhanced expression of interleukin (IL)-1 and IL-6 messenger RNA and bioactive protein after hypoxia-ischemia in neonatal rats. Rossi, D.

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J., Brady, J. D. & Mohr, C. Astrocyte metabolism and signaling during brain ischemia. Juul, S. E. & Ferriero, D. M. Pharmacologic neuroprotective strategies in neonatal brain injury. & Zhang, J. H. Neuroprotective strategies after neonatal hypoxic ischemic encephalopathy. & Zhang, L. Brain-immune interactions in perinatal hypoxic-ischemic brain injury. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Role of neuroinflammation in adult neurogenesis and Alzheimer disease: Therapeutic approaches. Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white oral sildenafil matter injury. Astrocyte-derived proinflammatory cytokines induce hypomyelination in the periventricular white matter in the hypoxic neonatal brain. Guadagno, J., Swan, P., Shaikh, R. & Cregan, S. P. Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells. Wyatt, J. S. Mechanisms of brain injury in the newborn. White matter injury in term newborns with neonatal encephalopathy. Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. Woodward, L.

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J., Anderson, P. J., Austin, N. C., Howard, K. & Inder, T. E. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice. & Golombek, D. A. Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules. Sildenafil treatment of vascular dementia in aged rats. The functional and structural consequences of cavernous nerve injury are ameliorated by sildenafil citrate.J. Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95. Sildenafil citrate improves erectile function after castration in a rat model. Hutchings, D. C., Anderson, S. G., Caldwell, J. L. & Trafford, A. W. Phosphodiesterase-5 inhibitors and the heart: Compound cardioprotection?. Narayanan, S. P., Flores, A. I., Wang, F. & Macklin, W.

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Neurobiology of hypoxic-ischemic injury in the developing brain. Relationship between evolving epileptiform activity and delayed loss of mitochondrial activity after asphyxia measured by near-infrared spectroscopy in preterm fetal sheep. Gunn, A. J., Gunn, T. R., de Haan, H.

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H., Williams, C. E. & Gluckman, P. D. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.

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& Gressens, P. Tertiary mechanisms of brain damage: A new hope for treatment of cerebral palsy?. & Charriaut-Marlangue, C. Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal Rat. Adenosine deaminase activity, lipid peroxidation and astrocyte responses in the cerebral cortex of rats after neonatal hypoxia ischemia. Feasibility and safety of sildenafil to repair brain injury secondary to birth asphyxia (SANE-01): A randomized, double-blind, placebo-controlled phase Ib clinical trial. Testing higher doses of sildenafil to repair brain injury secondary to birth asphyxia: An open-label dose-finding phase 1b clinical trial (SANE-02). Armin Yazdani received the 2015 IPN Returning Student Award, the 2016–2017 Doctoral Training Award from the Fonds de Recherche du Québec—Santé (FRQS) and the Foundation of Stars, and the 2017 Jewish Community Foundation of Montreal (JCF) Steven Zalcman Memorial Scholarship. Virginie Bleau received a McEntyre Summer Research Bursary and a Nicholas McCutcheon Summer Research Bursary in Medicine. Yandi Zheng received a 2018 Canada Summer Job. Palig Balian received the 2017 Graduate Student Performance Award from the FRQS Vision Health Research Network (VHRN), the 2017–2018 RI MUHC Desjardins Studentship in Child Health Research Award, and the 2018 Frederick Banting and Charles Best Canada Graduate Scholarship – Master’s (CGS M) from the Canadian Institutes of Health Research (CIHR). Pia Wintermark holds a William Dawson Scholar Award from the McGill Faculty of Medicine and Health Sciences and her research work is supported by a CIHR Project Grant and a donation from the Courtois Foundation through the Montreal Children’s Hospital Foundation. AY, VB and RS planned and executed the animal experiments, collected the data, analyzed and interpreted them; they drafted the first version of the manuscript, and approved the final manuscript as submitted.

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All data generated during this study are included in this published article. Kurinczuk, J. J., White-Koning, M. & Badawi, N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy.

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& Stinson, D. A. Hypothermia for neonatal hypoxic ischemic encephalopathy: An updated systematic review and meta-analysis. Moderate hypothermia to treat perinatal asphyxial encephalopathy. & Nakajima, W. YZ and PB contributed to some animal experiments and analysis; they critically reviewed the manuscript, and approved the final manuscript as submitted. ZK contributed to the animal surgery and tissue collection, critically reviewed the manuscript, and approved the final manuscript as submitted. PW acquired funding, conceptualized and designed the study, analyzed some of the data, supervised the students in the collection and analysis of other data, interpreted the results, drafted the initial manuscript, revised it according to comments, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material.

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