Angela Saadat, Haree Pallera, Frank Lattanzio, Daley Owens, Amy Gaines, Sai Susmitha Ravi, Tushar Shah
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引用次数: 0
Abstract
Introduction: The complement response activates upon reperfusion in neonatal hypoxic-ischemic encephalopathy (HIE) and contributes to excessive neuroinflammation and worse outcomes. C5a is a powerful anaphylatoxin central to each of the complement pathways, and its engagement with C5aR1 is directly tied to brain injury and neuronal death. Reasoning C5aR1 antagonism can decrease excessive neuroinflammation and thereby improve neurological and functional outcomes, we tested this hypothesis in a rat model of HIE with PMX205, a small molecule that inhibits C5a-C5aR1 interaction.
Methods: Term-equivalent pups (P10-12) were subjected to mild-moderate HIE by Vannucci's method and treated with PMX205. We compared motor and cognitive outcomes with two behavioral tests each (food handling and accelerod; novel object recognition [NOR] and open field) to improve the accuracy of our conclusions.
Results: Improvements were observed in fine motor function, balance, and exploratory behaviors, but little to no improvement in recognition memory and gross motor function. Lesion area and histological assessments showed robust cortical neuroprotection from treatment but persistent injury to the CA1 region of the hippocampus. Better structural and functional outcomes were seen within 1 day of treatment, suggesting C5aR1 antagonism beyond the latent injury phase may impair recovery. In a dose-response experiment, cerebral area loss from injury was improved only in female rats, suggesting underlying sexual dimorphisms in the complement response.
Conclusion: These results demonstrate proof-of-concept for targeting C5aR1 signaling in neonatal HIE with PMX205 and underscore the role of sex in hypoxic-ischemic injury.
期刊介绍：
''Developmental Neuroscience'' is a multidisciplinary journal publishing papers covering all stages of invertebrate, vertebrate and human brain development. Emphasis is placed on publishing fundamental as well as translational studies that contribute to our understanding of mechanisms of normal development as well as genetic and environmental causes of abnormal brain development. The journal thus provides valuable information for both physicians and biologists. To meet the rapidly expanding information needs of its readers, the journal combines original papers that report on progress and advances in developmental neuroscience with concise mini-reviews that provide a timely overview of key topics, new insights and ongoing controversies. The editorial standards of ''Developmental Neuroscience'' are high. We are committed to publishing only high quality, complete papers that make significant contributions to the field.
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