Brain Natriuretic Peptide Improves Long-Term Functional Recovery after Acute CNS Injury in Mice

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2010-01

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Abstract

There is emerging evidence to suggest that brain natriuretic peptide (BNP) is elevated after acute brain injury, and that it may play an adaptive role in recovery through augmentation of cerebral blood flow (CBF). Through a series of experiments, we tested the hypothesis that the administration of BNP after different acute mechanisms of central nervous system (CNS) injury could improve functional recovery by improving CBF. C57 wild-type mice were exposed to either pneumatic-induced closed traumatic brain injury (TBI) or collagenase-induced intracerebral hemorrhage (ICH). After injury, either nesiritide (hBNP) (8 μg/kg) or normal saline were administered via tail vein injection at 30 min and 4 h. The mice then underwent functional neurological testing via rotorod latency over the following 5 days and neurocognitive testing via Morris water maze testing on days 24–28. Cerebral blood flow (CBF) was assessed by laser Doppler from 25 to 90 min after injury. After ICH, mRNA polymerase chain reaction (PCR) and histochemical staining were performed during the acute injury phase (<24 h) to determine the effects on inflammation. Following TBI and ICH, administration of hBNP was associated with improved functional performance as assessed by rotorod and Morris water maze latencies (p < 0.01). CBF was increased (p < 0.05), and inflammatory markers (TNF-α and IL-6; p < 0.05), activated microglial (F4/80; p < 0.05), and neuronal degeneration (Fluoro-Jade B; p < 0.05) were reduced in mice receiving hBNP. hBNP improves neurological function in murine models of TBI and ICH, and was associated with enhanced CBF and downregulation of neuroinflammatory responses. hBNP may represent a novel therapeutic strategy after acute CNS injury.

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Michael L. James, Haichen Wang, Talaignair Venkatraman, Pingping Song, Christopher D. Lascola, and Daniel T. Laskowitz. Journal of Neurotrauma. January 2010, 27(1): 217-228

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10.1089/neu.2009.1022

Publication Info

James, Michael L, Haichen Wang, Talaignair Venkatraman, Pingping Song, Christopher D Lascola and Daniel T Laskowitz (2010). Brain Natriuretic Peptide Improves Long-Term Functional Recovery after Acute CNS Injury in Mice. 10.1089/neu.2009.1022 Retrieved from https://hdl.handle.net/10161/5971.

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Scholars@Duke

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.

Wang

Haichen Wang

Assistant Professor in Neurology
Lascola

Christopher David Lascola

Associate Professor of Radiology
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.


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