Effects of polyphenols on neonatal HI brain injury Funded Grant uri icon

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  • Injury to the developing brain due to hypoxia-ischemia (H-l) is a significant cause of morbidity and mortality often leading to intellectual impairment, motor abnormalities, and seizures. Animal models are useful to investigate mechanisms underlying Hl-related injury as well as to develop treatments. A well characterized model of HI induced neonatal brain injury in small mammals involves unilateral carotid ligation followed by systemic exposure to hypoxia. This insult results in histological brain injury to the hemisphere ipsilateral to carotid ligation that has many similarities to what is seen in the developing human brain following HI. It is often difficult to identify infants that are undergoing H-l in a timely or predictable fashion. There are some situations, however, where there is a very high risk for injury to the developing brain after birth such as in the weeks following birth of very premature babies or in premature or term infants that require particular types of surgery. Thus, development of approaches to protect the developing brain exposed to H-l would include providing treatments 1) to high risk pregnant mothers or 2) to premature and term infants that either are or are likely to be exposed to H-l. We have found that feeding pregnant mice a natural food substance, pomegranate juice (PJ), is neuroprotective to P7 mice exposed to H-l. PJ has amongst the highest concentrations of polyphenols present in fruits and other foods. We have also found that the specific polyphenols, resveratrol and caffeic acid phenylester (CAPE), are neuroprotective when administered systemically to P7 mice and rats subjected to neonatal H-l. Studies suggest that polyphenols may be having their effects via the histone deacetylase, SIRT1. We hypothesize that exposure to polyphenols from PJ as well as the specific polyphenols resveratrol and CAPE will protect the neonatal brain against the acute effects of HI as well as promote long term recovery. In addition, we hypothesize that the neuroprotective effects of polyphenols including resveratrol are via SIRT1. We will explore the effects of PJ polyphenols, resveratrol, and CAPE in both acute injury and during recovery as well as mechanisms of neuroprotection using a mouse model of neonatal HI utilizing biochemical, histological, behavioral, and MRI assessments. The relevance of this research to public health is that it is attempting to discover treatments to decrease the neurological morbidity that occurs due to hypoxia-ischemia in both premature and term infants.