PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a devastating disease usually originating from hypoxia-ischemia (H-I) before birth. It has one of the very highest indices of burden of disease. The costs to society are huge, to the tune of $15 billion. Prevention of a single CP patient would save almost $1.2 million dollars, not factoring indirect costs to parents, siblings, communities and society from life-long commitments. The number of affected CP patients, 800,000 in USA, and burden of disease is higher than many adult neurological diseases affecting the twilight years. Yet, there is a paucity of effective therapies for CP. To solve the problems of finding new neuroprotectants that can be translated to the humans situation, we are proposing to test novel specific inhibitors of neuronal nitric oxide synthase (nNOS) in a rabbit model of cerebral palsy based on human acute placental insufficiency and the clinical paradigm of placental abruption. These new nNOS inhibitors are the most potent neuroprotectants found in our laboratory. We utilize MRI biomarkers that inform us about the immediate fetal brain response to H-I and reliably predict which rabbit fetuses will manifest motor deficits after delivery. We utilize recent advances in detecting oxidative and nitrosative stress (caused by reactive nitrogen species derived from nitric oxide). Instead of a zero-sum way of looking at oxidative stress and antioxidants, we posit the biphasic nature of reactive species in brain cell function and that a dance between various oxidants and antioxidants is necessary for critical brain injury. We hypothesize that the timing and location of nitrosative stress in important in determining which fetuses will develop motor deficits. The proposed studies will lead to the development of a neuroprotective strategy that can also be used in resource-poor countries in addition to developed countries. The first Aim will determine the nature of gray and white matter injury in the fetal brain. The second Aim will determine whether nitric oxide derived from nNOS is responsible for the critical brain injury that results in motor deficits. The third Aim will determine the best candidate drug to take to clinical trials. The new innovations proposed are the systemic integration of MRI as a surrogate marker and high speed sorting into the unique animal model to probe the biochemical basis of specific neuronal injury at a critical time point. The clinical importance of this proposal is that the studies will select the most potent and non-toxic drug in the class of nNOS inhibitors for preventing motor deficits. The proposed studies will thus provide the systematic development of much-needed therapies for CP not only in USA but throughout the world.