Injury to the developing brain due to hypoxia-ischemia (H-l) is a significant cause of morbidity and mortalityoften leading to intellectual impairment, motor abnormalities, and seizures. Animal models are useful toinvestigate mechanisms underlying Hl-related injury as well as to develop treatments. A well characterizedmodel of HI induced neonatal brain injury in small mammals involves unilateral carotid ligation followed bysystemic exposure to hypoxia. This insult results in histological brain injury to the hemisphere ipsilateral tocarotid ligation that has many similarities to what is seen in the developing human brain following HI. It isoften difficult to identify infants that are undergoing H-l in a timely or predictable fashion. There are somesituations, however, where there is a very high risk for injury to the developing brain after birth such as in theweeks following birth of very premature babies or in premature or term infants that require particular types ofsurgery. Thus, development of approaches to protect the developing brain exposed to H-l would includeproviding treatments 1) to high risk pregnant mothers or 2) to premature and term infants that either are orare 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 highestconcentrations of polyphenols present in fruits and other foods. We have also found that the specificpolyphenols, resveratrol and caffeic acid phenylester (CAPE), are neuroprotective when administeredsystemically to P7 mice and rats subjected to neonatal H-l. Studies suggest that polyphenols may be havingtheir effects via the histone deacetylase, SIRT1. We hypothesize that exposure to polyphenols from PJ aswell as the specific polyphenols resveratrol and CAPE will protect the neonatal brain against the acuteeffects of HI as well as promote long term recovery. In addition, we hypothesize that the neuroprotectiveeffects 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 neuroprotectionusing 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 theneurological morbidity that occurs due to hypoxia-ischemia in both premature and term infants.
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