AGMATINASE INHIBITORS FOR HYPOXIC-ISCHEMIC NEW BORN BRAIN DAMAGE

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DESCRIPTION (provided by applicant): Low blood flow and low oxygen to the brain (cerebral hypoxia-ischemia) is the putative etiology of brain injury in premature and term infants. This important clinical problem is a major cause of cerebral palsy, and no therapy is yet available. A wealth of evidence indicates that most of the brain damage in this situation is due to a rise in glutamate levels around the area of low blood perfusion. Glutamate antagonism by any of several mechanisms can ameliorate the penumbra of damage. However, the available synthetic glutamate receptor antagonists are poorly tolerated. A natural and milder agent may exist in agmatine, the decarboxylation product of L-arginine. Agmatine was only recently discovered to be synthesized in the brain. It has been shown that brain agmatine concentrations are increased during hypoxia-ischemia which maybe a natural defense mechanism of the brain since the substance is an endogenous antagonist of excitatory N-methyl-D-aspartate (NMDA) receptors as well as an inhibitor or the inducible form of nitric oxide synthase (NOS), which is pro-inflammatory. In fact, experimental treatments have revealed that agmatine injections are neuroprotective to rat pups, in vivo, and agmatine will directly protect neurons in culture. However, getting enough of an injection of agmatine into the brain leads to systemically high levels of agmatine which leads to unwanted side effects. To overcome this we are proposing that agents that selectively block agmatinase would raise endogenous pools of agmatine only where most needed. This is because agmatine levels in the brain are regulated by its degradative enzyme, agmatinase. We prepared a series of synthetic compounds and subjected them to analysis of quantitative structure activity relationships (QSAR). Linear correlations were obtained using geometric and electronic descriptors of each atom to predict a class of compounds with selectivity for agmatinase. Specific Aim 1 will test the first compound which we have already synthesized, designated APG, for neuroprotective efficacy in rat pups exposed to hypoxia-ischemia. Specific Aim-2 will use short-interfering RNA technology to diminish agmatinase in cells and be neuroprotective. Specific Aim-3 will determine if the other synthetic compounds act directly on cultured neurons. Specific Aim-4 will test which of the compounds is most neuroprotective in rat pups exposed to hypoxia-ischemia. The overall goal of these studies is to develop a treatment for perinatal brain damage in human infants.