Abstract
Background: Hypoxic-ischemic (HI) encephalopathy is a major cause of neonatal mortality and morbidity, with a global incidence of 3 per 1,000 live births. Intrauterine or perinatal complications, including maternal infection, constitute a major risk for the development of neonatal HI brain damage. During HI, inflammatory response and oxidative stress occur, causing subsequent cell death. The presence of an infection sensitizes the neonatal brain, making it more vulnerable to the HI damage. Currently, therapeutic hypothermia is the only clinically approved treatment available for HI encephalopathy, however it is only partially effective in HI alone and its application in infection-sensitized HI is debatable. Therefore, there is an unmet clinical need for the development of novel therapeutic interventions for the treatment of HI. Such an alternative is targeting the complement system. Properdin, which is involved in stabilization of the alternative pathway convertases, is the only known positive regulator of alternative complement activation. Absence of the classical pathway in the neonatal HI brain is neuroprotective. However, there is a paucity of data on the participation of the alternative pathway and in particular the role of properdin in HI brain damage.Objectives: Our study aimed to validate the effect of global properdin deletion in two mouse models: HI alone and LPS-sensitized HI, thus addressing two different clinical scenarios.Results: Our results indicate that global properdin deletion in a Rice-Vannucci model of neonatal HI and LPS-sensitized HI brain damage, in the short term, clearly reduced forebrain cell death and microglial activation, as well as tissue loss. In HI alone, deletion of properdin reduced TUNEL+ cell death and microglial post-HI response at 48 h post insult. Under the conditions of LPS-sensitized HI, properdin deletion diminished TUNEL+ cell death, tissue loss and microglial activation at 48 h post-HI.Conclusion: Overall, our data suggests a critical role for properdin, and possibly also a contribution in neonatal HI alone and in infection-sensitized HI brain damage. Thus, properdin can be considered a novel target for treatment of neonatal HI brain damage.
Highlights
Oxygen deprivation around the time of birth is a major cause of neonatal hypoxic ischemic (HI) brain damage affecting 1–3 per 1,000 live births in developed countries and increasing to 26 per 1,000 in the developing world [1]
Assessment of ipsilateral astrogliosis through glial fibrillary acidic protein (GFAP) immunoreactivity (Figure 1G) showed that compared to wild type controls (Figure 1H), global properdin deletion had no effect on reactive astrogliosis (Figure 1I) following neonatal HI
In addition to cell death, global properdin deletion had a significant effect on ipsilateral microglia activation score (Figure 1J) based on αM integrin immunoreactivity (Figures 1K,L)
Summary
Oxygen deprivation around the time of birth is a major cause of neonatal hypoxic ischemic (HI) brain damage affecting 1–3 per 1,000 live births in developed countries and increasing to 26 per 1,000 in the developing world [1]. Therapeutic hypothermia is the only clinically approved treatment available for HI encephalopathy, it is only partially effective in HI alone and its application in infection-sensitized HI is debatable. There is an unmet clinical need for the development of novel therapeutic interventions for the treatment of HI. Such an alternative is targeting the complement system. There is a paucity of data on the participation of the alternative pathway and in particular the role of properdin in HI brain damage
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