Abstract
Perinatal hypoxic ischemic encephalopathy (HIE) remains a major contributor of infant death and long-term disability worldwide. The role played by the complement system in this ischemia-reperfusion injury remains poorly understood. In order to better understand the role of complement activation and other modifiable mechanisms of injury in HIE, we tested the dual-targeting anti-inflammatory peptide, RLS-0071 in an animal model of HIE. Using the well-established HIE rat pup model we measured the effects of RLS-0071 during the acute stages of the brain injury and on long-term neurocognitive outcomes. Rat pups subject to hypoxia-ischemia insult received one of 4 interventions including normothermia, hypothermia and RLS-0071 with and without hypothermia. We measured histopathological effects, brain C1q levels and neuroimaging at day 1 and 21 after the injury. A subset of animals was followed into adolescence and evaluated for neurocognitive function. On histological evaluation, RLS-0071 showed neuronal protection in combination with hypothermia (P = 0.048) in addition to reducing C1q levels in the brain at 1hr (P = 0.01) and at 8 hr in combination with hypothermia (P = 0.005). MRI neuroimaging demonstrated that RLS-0071 in combination with hypothermia reduced lesion volume at 24 hours (P<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<0.01). RLS-0071 alone or in combination with hypothermia improved both short-term and long-term memory. These findings suggest that modulation by RLS-0071 can potentially decrease brain damage resulting from HIE.
Highlights
Perinatal asphyxia with moderate to severe hypoxic ischemic encephalopathy (HIE) is a significant public health concern worldwide with varying incidence in high, middle- and lowincome countries
The group receiving RLS-0071 at 5mg/kg x 2 showed gross infarction in 3 of 4 pups (75%) and the group receiving RLS-0071 at 10 mg/kg × 2 group showed gross infarction in 2 of 4 pups (50%). These data show a dose response suggesting that dosing with RLS-0071 at 10 mg/kg × 2 is the least effective dose at modulating HIE related gross findings in this animal model
There was no statistical difference between the medians for familiar and novel object indices for either NT or HT. Both RLS-0071 (p = 0.018) and HT+RLS-0071 (p = 0.01) showed significant differences between their indices, demonstrating improved long-term object memory (Fig 5A). These findings suggest that treatment with RLS-0071, with or without hypothermia, improved long term object memory compared with normothermia or hypothermia alone
Summary
Perinatal asphyxia with moderate to severe hypoxic ischemic encephalopathy (HIE) is a significant public health concern worldwide with varying incidence in high-, middle- and lowincome countries. 1-2/1000 live-births are affected in the developed world with an eight-fold higher incidence in the under developed countries [1]. 10–60% of affected infants die worldwide and at least 25% of survivors are affected with significant neurodevelopmental disabilities [2]. Complement inhibition reduces hypoxic ischemic encephalopathy have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section
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