Tumor necrosis factor α antagonism improves neurological recovery in murine intracerebral hemorrhage.

Abstract

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype characterized by a prominent neuroinflammatory response. Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH. To test this hypothesis, the tumor necrosis factor alpha (TNF-α) antibody CNTO5048 was administered to mice after ICH induction, and histological and functional endpoints were assessed. METHODS: Using 10 to 12-week-old C57BL/6J male mice, ICH was induced by collagenase injection into the left basal ganglia. Brain TNF-α concentration, microglia activation/macrophage recruitment, hematoma volume, cerebral edema, and rotorod latency were assessed in mice treated with the TNF-α antibody, CNTO5048, or vehicle. RESULTS: After ICH induction, mice treated with CNTO5048 demonstrated reduction in microglial activation/macrophage recruitment compared to vehicle-treated animals, as assessed by unbiased stereology (P = 0.049). This reduction in F4/80-positive cells was associated with a reduction in cleaved caspase-3 (P = 0.046) and cerebral edema (P = 0.026) despite similar hematoma volumes, when compared to mice treated with vehicle control. Treatment with CNTO5048 after ICH induction was associated with a reduction in functional deficit when compared to mice treated with vehicle control, as assessed by rotorod latencies (P = 0.024). CONCLUSIONS: Post-injury treatment with the TNF-α antibody CNTO5048 results in less neuroinflammation and improved functional outcomes in a murine model of ICH.

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Citation

Published Version (Please cite this version)

10.1186/1742-2094-10-103

Publication Info

Lei, Beilei, Hana N Dawson, Briana Roulhac-Wilson, Haichen Wang, Daniel T Laskowitz and Michael L James (2013). Tumor necrosis factor α antagonism improves neurological recovery in murine intracerebral hemorrhage. J Neuroinflammation, 10. p. 103. 10.1186/1742-2094-10-103 Retrieved from https://hdl.handle.net/10161/14240.

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Scholars@Duke

Wang

Haichen Wang

Assistant Professor in Neurology
Laskowitz

Daniel Todd Laskowitz

Professor of Neurology

Our laboratory uses molecular biology, cell culture, and animal modeling techniques to examine the CNS response to acute injury. In particular, our laboratory examines the role of microglial activation and the endogenous CNS inflammatory response in exacerbating secondary injury following acute brain insult. Much of the in vitro work in this laboratory is dedicated to elucidating cellular responses to injury with the ultimate goal of exploring new therapeutic interventions in the clinical setting of stroke, intracranial hemorrhage, and closed head injury.

In conjunction with the Multidisciplinary Neuroprotection Laboratories, we also focus on clinically relevant small animal models of acute CNS injury. For example, we have recently characterized murine models of closed head injury, subarachnoid hemorrhage, intracranial hemorrhage and perinatal hypoxia-ischemia, in addition to the standard rodent models of focal stroke and transient forebrain ischemia. Recently we have adapted several of these models from the rat to the mouse to take advantage of murine transgenic technology. The objective of these studies are two-fold: to gain better insight into the cellular responses and pathophysiology of acute brain injury, and to test novel therapeutic strategies for clinical translation. In both cell culture systems and animal models, our primary focus is on examining the role of oxidative stress and inflammatory mechanism in mediating brain injury following acute brain insult, and examining the neuroprotective effects of endogenous apolipoprotein E in the injured mammalian central nervous system.

Our laboratory is committed to translational research, and has several active clinical research protocols, which are designed to bring the research performed in the Multidisciplinary Research Laboratories to the clinical arena. These protocols are centered around patients following stroke and acute brain injury, and are primarily based out of the Emergency Room and Neurocritical Care Unit. For example, we are currently examining the role of inflammatory mediators for use as a point-of-care diagnostic marker following stroke, intracranial hemorrhage, and closed head injury. We have recently translated a novel apoE mimetic from the preclinical setting to a multi center Phase 2 trial evaluating efficacy in intracranial hemorrhage. We are also examining the functional role of different polymorphisms of of inflammatory cytokines in the setting of acute brain injury and neurological dysfunction following cardiopulmonary bypass.

James

Michael Lucas James

Professor of Anesthesiology

With a clinical background in neuroanesthesia and neurointensive care, I have a special interest in translational research in intracerebral hemorrhage and traumatic brain injury. I am fortunate to be part of a unique team of highly motivated and productive individuals who allow me to propel ideas from bench to bedside and the ability to reverse translate ideas from the bedside back to the bench.


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