Neonatal encephalopathy affects 1-2/1000 live term births and a greater number of preterm infants, including the late-gestation preterm. Therapeutic hypothermia is now standard of care for term infants with presumed hypoxia-ischemia (HI) when initiated within 6 hours of life. However, neuroprotection is incomplete and there is vital need fo adjunct therapies. Therapeutic hypothermia is not approved for preterm infants (less than 36 week gestation);currently there is no intervention for this at-risk group of infants. Mast cells ae multifunctional immune cells that originate as pluripotent progenitor cells in the bone marrow, and migrate to a variety of tissues where they mature and become terminally differentiated. Mast cells contained preformed mediators, including TNF-alpha, which is released on activation/ degranulation. Although mast cells have been best characterized in peripheral tissues, their activity in the CNS is gaining increasing appreciation. Mast cells migrate to the pia in response to a variety of signals, including hypoxia, and enter the brain parenchyma. Brain mast cell numbers are highest in the developing brain. Recent studies have highlighted mast cell involvement in stroke, MS, traumatic brain injury. We recently demonstrated that mast cells are early responders to hypoxia-ischemia in the neonatal rat;early, acute inhibition of mast cell migration and activation with the FDA approved drug Cromolyn provides longterm histologic neuroprotection and supports normal growth of the ischemic hemisphere. The goal of these studies is to extend this finding to the term-equivalent P10 rat and to complete additional necessary studies in this preclinical model to support studies in a large animal model and ultimately Phase 1 clinical trials. To achieve this goal, this translational R21 will pursue 3 Specific Aims: 1) Careful dose-response studies in both the P7 (late-gestation, preterm equivalent) and P10 (term equivalent) rat to evaluate Cromolyn efficacy in mast cell stabilization and neuroprotection after HI;2) combine Cromolyn administration with post-HI hypothermia in the P10 rat to investigate synergism in neuroprotection;3) sensorimotor and cognitive behavioral studies, with special attention to lateralization and hemispheric asymmetry, to establish longterm functional protection with Cromolyn in both P7 and P10 HI models. Successful completion of these studies should provide sufficient preclinical data to support a U01 grant application leading to an IND for Cromolyn as a neuroprotective therapeutic agent.
Neonatal encephalopathy affects 1-2/1000 live term births and a greater number of preterm births, resulting in lifelong neurologic dysfunction in the survivors. Therapeutic hypothermia is the only available intervention but is only approved for term infants within the first 6 hours of life. Additional safe interventions are needed. Cromolyn provides neuroprotection in the immature rat HI model and might be useful clinically. These studies will generate preclinical data to support this. NOTE: The critiques and criterion scores from individual reviewers are provided below in an essentially unedited form. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion.
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