Translational stroke research
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Traumatic brain injuries and their associated treatments carry high cost in both financial impact and morbidity to human life. Recent studies and trials present promising results in reducing secondary injury in the days and weeks following the primary insult. A number of studies, both pre-clinical and clinical, have found that different populations of stem/progenitor cells result in a reduction of inflammation, maintenance of the blood brain barrier, and an overall improved prognosis. ⋯ The spleen has become an area of intense interest as an arena where therapeutic cells interact with reactive macrophages to cause system-level changes in immune activity. Additionally, the spleen enacts anti-inflammatory responses originating in the CNS, delivered through vagal activity with a recently described mechanism culminating in acetylcholine release. This review provides a summary of recent findings as to the mechanisms of action observed in current cellular therapies.
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Emerging evidence suggests sex and apolipoprotein E (APOE) genotype separately modify outcomes after intracerebral hemorrhage (ICH). We test the hypothesis that an interaction exists between sex and APOE polymorphism in modifying outcomes after ICH and is altered by administration of exogenous apoE-mimetic peptide. To define the effects of sex and APOE polymorphism in ICH, we created collagenase-induced ICH in male and female APOETR mice (targeted replacement mice homozygous for APOE3 or APOE4 alleles; n=12/group) and assessed performance on Rotarod (RR) and Morris water maze (MWM). ⋯ Administration of a therapeutic apoE-mimetic peptide improved RR latencies through 7 days after ICH in male and female APOE4TR mice and MWM latencies over days 28-32 after ICH in male APOE4TR mice (p<0.05). Sex and APOE polymorphism influence functional outcomes in our murine model of ICH. Moreover, administration of exogenous apoE-mimetic peptide after injury differentially modifies the interaction between sex and APOE polymorphism.
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There is growing evidence supporting the role of inflammation in early brain injury and cerebral vasospasm following subarachnoid hemorrhage (SAH). Matrix metalloproteinases (MMPs) are released by inflammatory cells and can mediate early brain injury via disruption of the extracellular matrix and mediate vasospasm by cleaving endothelin-1 into vasoactive fragments. We hypothesize that inflammation marked by neutrophil elevation and MMP-9 release in human SAH is associated with vasospasm and with poor clinical outcome. ⋯ Blood and CSF MMP-9 are associated with clinical outcome but not with vasospasm, suggesting that MMP-9 may mediate brain injury independent of vasospasm in SAH. Future in vitro studies are needed to investigate the role of MMP-9 in SAH-related brain injury. Larger clinical studies are needed to validate blood and CSF MMP-9 as potential biomarkers for SAH outcome.
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Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. ⋯ The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call "syndromics", which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings.
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Stroke is the second leading cause of death worldwide and the third leading cause of death in the USA. A clinically useful biomarker for the diagnosis of stroke does not currently exist. Biomarkers could improve stroke care by allowing early diagnosis by non-expert clinical providers, serial monitoring of patients, and rapid assessment of severity of brain injury. ⋯ This will include the utility of neuroproteomics/neurosystems biology analysis as a novel discipline leading to the identification of novel biomarkers that can reach the pipeline of bench side. Additionally, an outline of biomarker-based management of traumatic brain injury and stroke patient assessments of therapeutic interventions has been included. Finally, comparison of current biomarker occurrence between preclinical models and biomarker data from human clinical studies for stroke has been summarized.