Developmental age specific neuroprotective therapies for perinatal brain injury

Perinatal brain injury such as hypoxic-ischemic encephalopathy (HIE) is associated with a high risk of mortality and morbidity including intellectual disability, cerebral palsy, epilepsy, hearing or vision impairment. No therapies currently for late preterm(34-36 weeks’ gestation) HIE , which falls in a research gap between term (37-40 weeks’ gestation) HIE treated with therapeutic hypothermia and preterm white matter injury frequently seen in infants born <32 weeks’ gestation. Importantly, even when the etiology of injury is similar, there is limited evidence to suggest that the same therapeutic strategy will be effective for late preterm and term infants born with 2-4 weeks’ difference in gestational age at birth. Our recent preliminary data in late preterm and term equivalent rat models of newborn brain injury suggests there is a loss of neuroprotective effect of an anti-inflammatory, anti-oxidant agent with increasing developmental age at onset of injury. To determine if developmentally specific therapies are needed for neonatal brain injury, our objective is to evaluate curcumin-encapsulated biodegradable nanoparticles with high curcumin loading (40% by weight) and controlled release in late preterm and term brain injury. Curcumin has antioxidant, anti-inflammatory, and anti-apoptotic effects; however, curcumin’s therapeutic applications are restricted due to low aqueous solubility, low bioavailability, instability in light, and rapid first-pass hepatic metabolism. Polymeric nanoparticles can provide high drug encapsulation efficiency and sustained release of a therapeutic, in addition to improving drug solubility, circulation kinetics, and parenchymal distribution and cellular uptake in the brain. We have shown upon systemic administration that curcumin-loaded poly(lactic- co-glycolic acid) poly(ethylene glycol) (PLGA-PEG) nanoparticles localized in injured regions of the brain and reduced acute neuronal and global brain injury after cerebral hypoxia-ischemia (HI) in a late preterm rat. Our overall hypothesis is that curcumin-loaded nanoparticles will lead to long-term reduction in neuroinflammation and oxidative stress, and improved behavioral outcomes after neonatal HI brain injury, with greater efficacy in the late-preterm model than the term model. In Aim 1, we will evaluate nanocurcumin for neuroprotection in late preterm and term neonatal HI brain injury. We will measure oxidative stress and inflammatory markers, and quantify PLGA-PEG and curcumin uptake and localization as a function of blood-brain-barrier impairment. We will then evaluate the neuroprotection afforded by two dosing schemes of cucumin-loaded PLGA-PEG in the late preterm and term neonatal HI model to determine the most effective dosing scheme for reducing global brain injury and total area loss, improving neuropathological outcomes, and mitigating inflammation and oxidative stress. Using the most effective dose from Aim 1, in Aim 2 we will assess long-term neuropathology and behavioral outcomes of curcumin neuroprotection in late preterm-equivalent rats after HI. Successful completion of this study will result in a promising nanotherapeutic platform for late preterm brain injury and inform therapeutic development for different developmental ages at injury onset. Project Number: 1R21HD118142-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Elizabeth Nance | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $406,020 | Activity Code: R21 | Study Section: Developmental Brain Disorders Study Section[DBD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11303808