Anticonvulsants for hypothermic neuroprotection in neonatal ischemic brain injury

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

[unreadable] DESCRIPTION (provided by applicant): This is a substantially revised R21 application, designed to address a clearly defined clinical question in a well-established preclinical model. The goal of this proposal, submitted in response to PAR-06-189, is to identify clinically feasible interventions that increase the neuroprotective efficacy of induced hypothermia after neonatal hypoxic-ischemic brain injury. In both infants and adults, moderate hypothermia improves neurological outcome after acute asphyxial brain injury. However, in two recent neonatal hypothermia trials, even with cooling, over 40% of treated infants had abnormal neurological outcomes at 18 months. Thus, it is a very high clinical priority to develop therapeutic interventions to improve the neuroprotective efficacy of cooling. We hypothesize that early treatment with anticonvulsants will augment the efficacy of therapeutic hypothermia. Experiments will be carried out in a well-characterized neonatal rodent model of hypoxic- ischemic brain injury, unilateral carotid artery ligation, followed by timed exposure to moderate hypoxia (8% oxygen, 1.5 hours) in 7 day old (P7) rats of both genders, and will incorporate functional (sensorimotor and cognitive) and neuropathological outcome measures. One critical factor that limits the neuroprotective efficacy of post-asphyxial cooling is the inevitable time interval between the hypoxic-ischemic event and the opportunity to begin treatment. Our goal is to identify drugs that extend the therapeutic window for initiation of hypothermic neuroprotection. The rationale stems from a study in which we replicated this clinically important lag period in the animal model, by delaying onset of cooling until 3 hours after the insult. In this model, 3 hours of cooling, initiated immediately after hypoxia-ischemia, reduces acute brain injury; in contrast, if cooling is initiated 3 hours later ("delayed- cooling") it is ineffective. However, the combination of treatment with topiramate, an anticonvulsant with multiple modes of action, within 15 min after hypoxia-ischemia and delayed cooling resulted in long-term neuroprotection. Yet, since no parenteral formulation of topiramate is available, these findings provide a compelling impetus for identification of other drugs with similar efficacy. Since seizures are common in asphyxiated neonates, and there is evidence that they exacerbate brain injury, we propose to evaluate other antiepileptic drugs. In Aim 1, we will evaluate 4 clinically available anticonvulsants, and determine which agents extend the therapeutic window for initiation of hypothermia after neonatal hypoxic-ischemic brain injury. We will also determine if selected drugs are more effective if there is a shorter delay period (one hour) before the onset of cooling. In Aim 1 sensorimotor and pathological outcomes will be evaluated after a one week recovery period. In Aim 2 we will incorporate functional (sensorimotor and cognitive) and pathological outcomes and determine if neuroprotection is sustained one month later. Results of these experiments can be readily translated to other pre-clinical and ultimately to clinical applications. The aim of this study is to determine if early treatment with anticonvulsants can extend the time window for initiation of effective and safe hypothermia-mediated neuroprotection in neonates. The proposed research will use a well-characterized neonatal rodent model of hypoxic-ischemic brain injury. Our long term goal is to identify effective, safe, and feasible treatment strategies that can be rapidly translated into clinical practice and that will limit the adverse impact of hypoxic-ischemic brain injury in neonates and infants. [unreadable] [unreadable] [unreadable]