Minimizing central nervous system (CNS) injury from preterm birth depends upon understanding the critical pathways that underlie essential neurodevelopmental and CNS pathophysiology. Signaling by chemokine (C-X-C motif) ligand 1 (CXCL1) through its cognate receptor, CXCR2 [(C-X-C motif) receptor 2] is essential for neurodevelopment. Increased CXCR2 signaling, however, is implicated in a variety of uterine and neuropathologies, and their role in the CNS injury associated with perinatal brain injury is poorly defined. To evaluate the long-term efficacy of CXCR2 blockade in functional repair of brain injury secondary to chorioamnionitis (CHORIO), we used an established preclinical rat model of cerebral palsy. We tested the hypothesis that transient postnatal CXCR2 antagonism with SB225002 would reduce gait deficits, hypermobility, hyperactivity, and disinhibition concomitant with repair of functional and anatomical white and gray matter injury. CHORIO was induced in pregnant Sprague Dawley rats on embryonic day 18 (E18). SB225002 (3 mg/kg) was administered intraperitoneally from postnatal day 1 (P1)-P5. Rats were aged to adulthood and tested for gait, open-field behavior and cognitive and executive function deficits using a touchscreen cognitive assessment platform. Results show that transient CXCR2 blockade attenuated microstructural white matter injury after CHORIO consistent with improved anatomical connectivity, and mitigated deficits in gait coordination, posture, balance, paw placement, and stepping (p < 0.05). Animals with CHORIO were hyperactive and hypermobile with fMRI deficits in neural circuitry central to cognition. However, CXCR2 antagonism in CHORIO animals did not normalize open-field behavior, neural activity, or cognition on a touchscreen task of discrimination learning (all p > 0.05). Studies in CXCR2 knockout mice confirmed significantly impaired cognitive performance independent of CHORIO. Taken together, transient postnatal blockade of CXCR2 ameliorates aspects of the lasting neural injury after CHORIO including normalizing gait deficits and white matter injury. However, improvement in essential functional and cognitive domains are not achieved limiting the utility of this therapeutic approach for treatment of perinatal brain injury. This study emphasizes the complex, multi-faceted role of chemokines in typical neurodevelopment, circuit formation, neural network function, and injury response.
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http://dx.doi.org/10.1111/jnc.16253 | DOI Listing |
Crit Care
December 2024
Département d'anesthésie Réanimationéanimation, DMU PARABOL, AP-HP, Hôpital Beaujon, Clichy, France.
Acta Biomater
December 2024
Institute for Vision Research, Carver College of Medicine; University of Iowa, Iowa City, IA; Department of Ophthalmology and Visual Sciences, Carver College of Medicine University of Iowa, Iowa City, IA. Electronic address:
In retinal diseases such as age-related macular degeneration (AMD) and choroideremia, a key pathophysiologic step is loss of endothelial cells of the choriocapillaris. Repopulation of choroidal vasculature early in the disease process may halt disease progression. Prior studies have shown that injection of donor cells in suspension results in significant cellular efflux and poor cell survival.
View Article and Find Full Text PDFNeurotherapeutics
December 2024
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Neurocritical Care Division, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, MD, United States; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address:
Brain ischemia is a major cause of neurological dysfunction and mortality worldwide. It occurs not only acutely, such as in acute ischemic stroke (AIS), but also in chronic conditions like cerebral small vessel disease (cSVD). Any other conditions resulting in brain hypoperfusion can also lead to ischemia.
View Article and Find Full Text PDFBMC Med Res Methodol
December 2024
Division of Biostatistics, Department of Population Health, New York University Grossman School of Medicine, 180 Madison Avenue, New York, NY, USA.
Background: In cohort studies with time-to-event outcomes, covariates of interest often have values that change over time. The classical Cox regression model can handle time-dependent covariates but assumes linear effects on the log hazard function, which can be limiting in practice. Furthermore, when multiple correlated covariates are studied, it is of great interest to model their joint effects by allowing a flexible functional form and to delineate their relative contributions to survival risk.
View Article and Find Full Text PDFMol Neurobiol
December 2024
Department of Pediatrics, the Second School of Medicine, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
White matter injury (WMI) is a common complication of preterm birth, potentially resulting in long-term behavioral and motor abnormalities. The objective of this study is to investigate the neuroprotective effects of glycyrrhizin (GLY) on WMI, and try to elucidate the potential mechanisms. In vivo chronic hypoxia-induced WMI mouse model and in vitro oxygen-glucose deprivation (OGD) induced WMI cell model were established, and the effects of GLY on WMI were explored through multiple assays, such as western blotting, immunofluorescence, immunohistochemistry, behavioral experiments, real-time quantitative polymerase chain reaction (RT-qPCR), transmission electron microscope (TEM), molecular docking, and bioinformatics analysis.
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