权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Drug Repurposing to Accelerate Progress in Neonatal Neuroprotection

药物再利用加速新生儿神经保护的进展

基本信息

批准号：
10454287
负责人：
JOHN D BARKS
金额：
$ 19.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454287
关键词：
Acute Brain Injuries Address Adolescent Adverse effects Advocate Age Agonist Animal Model Animals Antibiotics Attenuated Azithromycin Brain Brain Hypoxia-Ischemia Brain Injuries Caffeine Carotid Arteries Cessation of life Childhood Clinical Clinical Trials Cognitive deficits Complex Consultations Contralateral Corpus striatum structure Data Development Dose Ensure Erythropoietin Evaluation Event Experimental Animal Model Exposure to FDA approved Funding Goals Hippocampus (Brain)Histopathology Human Hypoxia Hypoxic-Ischemic Brain Injury Infant Infarction Infection Inflammation Inflammatory Injections Injury Intervention Ipsilateral Ischemia Laboratories Lesion Life Ligation Lipopolysaccharides Mammals Measures Melatonin Memory Methods Modeling Morbidity - disease rate Necrotizing Enterocolitis Neonatal Neonatal Brain Injury Neurologic Neurologic Deficit Neuroprotective Agents Outcome Outcome Measure Oxygen Pathology Perinatal Brain Injury Pharmaceutical Preparations Pharmacotherapy Phase Phase III Clinical Trials Premature Infant Probability Procedures Property Prosencephalon Protocols documentation Publications Rattus Regimen Reperfusion Therapy Reporting Research Research Personnel Risk Rodent Rodent Model Safety Sample Size Sensorimotor functions Severities Side Standardization Stimulus Survivors TLR2 gene TLR4 gene Tetracyclines Therapeutic Time Tissues age group base brain tissue clinical efficacy comparative efficacy design disability drug candidate drug development drug repurposing efficacy study efficacy testing experimental study functional outcomes improved intraamniotic infection intrauterine infection ischemic injury model design natural hypothermia neonatal brain neonatal human neonatal hypoxic-ischemic brain injury neonatal infection neonatal period neonatal resuscitation neonate neuropathology neuroprotection novel strategies novel therapeutics perinatal injury postnatal premature preterm newborn primary outcome protective efficacy response sildenafil stem topiramate white matter white matter injury

项目摘要

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.

摘要