Drug Repurposing to Accelerate Progress in Neonatal Neuroprotection

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Abstract In childhood, the risks of acute brain injury peak in the neonatal period. Major mechanisms of perinatal brain injury include hypoxia-ischemia (HI) and inflammation in response to intrauterine (e.g. chorioamnionitis) or neonatal (e.g. necrotizing enterocolitis) infections. In term infants, antecedent hypoxic-ischemic events can often be discerned; in premature neonates, multifactorial contributing mechanisms are often more difficult to identify. In view of the significant neurologic morbidity associated with perinatal brain injury in both term and preterm infants, effective neuroprotective interventions are greatly needed. Many drugs decrease brain injury and improve functional outcome in neonatal rodent hypoxic-ischemic (HI) brain injury models. A major translational challenge is to select those to prioritize for advancement to complementary larger animal perinatal injury models, and ultimately to early stage human neonatal trials. In view of the time lag from new drug development to clinical trials, our strategy is to prioritize evaluation of potentially neuroprotective drugs that are already approved for other indications i.e. “repurposing”, and utilize an “adaptive platform design model” for comparative efficacy studies. This proposal builds upon our recent findings that treatment with a clinically available antibiotic, azithromycin (AZ), reduces brain damage and improves functional outcomes in multiple neonatal rodent hypoxic-ischemic (HI) brain injury models. Our aims are to compare neuroprotective efficacy among clinically available drugs, including AZ, that are neuroprotective in similar neonatal rodent models, to help prioritize the best candidate(s) to advance to human trials. Efficacy will be compared in well-characterized rat models of hypoxic-ischemic and inflammation-amplified hypoxic-ischemic brain injury. We will incorporate studies in two age groups, post-natal day 7 (P7), to model term brain development, and P3, to model premature neonates. To elicit unilateral forebrain injury, animals undergo unilateral carotid artery ligation and subsequent timed (45-90 min) exposure to 8% oxygen; this results in quantifiable sensorimotor deficits and unilateral brain tissue damage. Pro-inflammatory stimuli, e.g. injections of a TLR-4 (lipopolysaccharide, LPS) or a TLR-2 (Pam3CSK4) agonist prior to lesioning, amplify HI injury. Our preliminary studies showed that treatment with AZ confers dose and time-dependent neuroprotection, at both ages, vs. HI and inflammation- amplified HI injury. Our current goals are to compare the neuroprotective efficacy among multiple clinically available drugs (AZ, erythropoietin, melatonin, sildenafil, caffeine, topiramate) in P7 (Aim 1) and P3 (Aim 2) rat hypoxic-ischemic and inflammation-amplified hypoxic-ischemic brain injury models. We quantify protective efficacy with composite scores that incorporate lateralizing sensorimotor function, memory and neuropathology measures, and also account for death as a possible injury outcome. We hypothesize that these comparative efficacy studies will identify one or two drugs with the highest probability of superiority at each age, and thus accelerate progress towards advancing safe and effective drugs to clinical trials in term and preterm neonates.