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Background and Purpose: The only validated treatment to prevent brain damage associated with hypoxia-ischemia (HI) encephalopathy of the newborn is controlled hypothermia with limited benefits. Additional putative neuroprotective drug candidates include sildenafil citrate, a phosphodiesterase-type 5 inhibitor. The main objective of this preclinical study is to assess its ability to reduce HI-induced neuroinflammation, in particular through its potential effect on microglial activation., Methods: HI was induced in P10 Sprague-Dawley rats by unilateral carotid permanent artery occlusion and hypoxia (HI) and treated by either hypothermia (HT) alone, Sildenafil (Sild) alone or combined treatment (SildHT). Lesion size and glial activation were analyzed by immunohistochemistry, qRT-PCR, and proteomic analyses performed at P13., Results: None of the treatments was associated with a significant early reduction in lesion size 72h after HI, despite significant changes in tissue loss distribution. Significant reductions in both Iba1 + (within the ipsilateral hemisphere) and GFAP + cells (within the ipsilateral hippocampus) were observed in SildHT group, but not in the other treatment groups. In microglia-sorted cells, pro-inflammatory markers, i.e. Il1b, Il6, Nos2, and CD86 were significantly downregulated in SildHT treatment group only. These changes were restricted to the ipsilateral hemisphere, were not evidenced in sorted astrocytes, and were not sex dependent. Proteomic analyses in sorted microglia refined the pro-inflammatory effect of HI and confirmed a biologically relevant impact of SildHT on specific molecular pathways including genes related to neutrophilic functions., Conclusions: Our findings suggest that Sildenafil combined with controlled hypothermia produces maximum effect in mitigating microglial activation induced by HI through complex proteomic regulation. The reduction of neuroinflammation induced by Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection., (© 2024. The Author(s).) more...

Prematurity, observed in 15 million births worldwide each year, is a clinical condition that is a major cause of neonatal mortality and morbidity in the short and long term. Preterm infants are at high risk of developing respiratory problems, sepsis, and other morbidities leading to neurodevelopmental impairment and neurobehavioral disorders. Perinatal glucocorticosteroids have been widely used for the prevention and treatment of adverse outcomes linked to prematurity. However, despite their short-term benefits due to their maturational properties, some clinical trials have shown an association between steroids exposure and abnormal brain development in infants born preterm. Neuroinflammation has emerged as a preeminent factor for brain injury in preterm infants, and the major role of microglia, the brain resident immune cells, has been recently highlighted. Considering the role of microglia in the modulation of brain development, the aim of this review is to summarize the effects of endogenous and exogenous glucocorticosteroids on brain development and discuss the possible role of microglia as the mediator of these effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.) more...