In spinal cord injury (SCI), an innate cellular inflammatory response is induced that includes the invasion of phagocytes such as neutrophils. Neutrophils can cause secondary bystander injury to normal resident cells, inadvertently worsening the primary injury. MRP8/14, which comprises ~40% of neutrophil cytoplasmic protein, is released following neutrophil/ endothelium adhesion, and plays a crucial role in altering (damaging) the endothelial barrier to facilitate transendothelial migration of neutrophils The biological importance of MRP8/14 is well known, but molecular mechanism of intracellular trafficking and release of MRP8/14 from neutrophils are poorly understood. We made the unexpected discovery that the Sur1 antagonist, glibenclamide, administered as late as 12 hr after spinal cord trauma, reduces the number of neutrophils invading in the penumbra, leading to the novel hypothesis that Sur1 has a crucial role in neutrophil transmigration. Using a model of inflammation in which the CXCR2 ligand and potent neutrophil attractant, CXCL8, is injected directly into the spinal cord, we found in wild-type mice a robust invasion of neutrophils that was marked by significant TUNEL-positive cell death and neurological dysfunction. When the same experiment was repeated in Abcc8-/- mice, which lack Sur1, cell death, neutrophil invasion and neurological dysfunction were essentially eliminated, pointing to a crucial role of Sur1 in the neuroinflammatory response after SCI. Subsequent molecular experiments suggested that Sur1 physically co-associates with MRP8/14, and plays a critical role in the trafficking and release of MRP8/14 from neutrophils. The purpose of this competitive renewal is to expand upon these novel preliminary data, and to establish the role of Sur1 in neuroinflammation. DESCRIPTION:
In Specific Aim (SA) 1, we will use gene knockout mice to demonstrate the critical role of Sur1 and MRP8/14 in the cellular inflammatory response in the spinal cord following CXCL8 injection. In SA2, we will use WT mice administered vehicle or glibenclamide at late times after contusion SCI to demonstrate the protective affect of Sur1 inhibition as regards the cellular inflammatory response after SCI. In SA3 we will characterize the functional role of Sur1 in neutrophil secretion of MRP8/14, and we will characterize the molecular interaction between Sur1 and MRP8/14.

Public Health Relevance

Each year, SCI devastates the lives of thousands of people worldwide. Short of actual prevention, the best hope for reducing the impact of SCI rests with decreasing secondary injury suffered after trauma. Tremendous progress has been made in cell replacement therapies and rehabilitation, but these treatments work best when administered in the context of the smallest possible lesion. Neutrophil invasion into the penumbra is responsible for significant bystander injury, yet effective treatments to ameliorate neutrophil invasion are lacking. The purpose of this proposal is to demonstrate that inhibition of Sur1 can exert a significant salutary effect in SCI due to inhibition of neutrophil invasion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS060801-06
Application #
8576592
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Jakeman, Lyn B
Project Start
2007-12-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Gerzanich, Volodymyr; Makar, Tapas K; Guda, Poornachander Reddy et al. (2017) Salutary effects of glibenclamide during the chronic phase of murine experimental autoimmune encephalomyelitis. J Neuroinflammation 14:177
Hayman, Erik G; Wessell, Aaron; Gerzanich, Volodymyr et al. (2017) Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 26:301-310
Aarabi, Bizhan; Sansur, Charles A; Ibrahimi, David M et al. (2017) Intramedullary Lesion Length on Postoperative Magnetic Resonance Imaging is a Strong Predictor of ASIA Impairment Scale Grade Conversion Following Decompressive Surgery in Cervical Spinal Cord Injury. Neurosurgery 80:610-620
Grunwald, Zachary; Beslow, Lauren A; Urday, Sebastian et al. (2017) Perihematomal Edema Expansion Rates and Patient Outcomes in Deep and Lobar Intracerebral Hemorrhage. Neurocrit Care 26:205-212
Kurland, David B; Gerzanich, Volodymyr; Karimy, Jason K et al. (2016) The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia. J Neuroinflammation 13:130
Urday, Sebastian; Beslow, Lauren A; Dai, Feng et al. (2016) Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage. Crit Care Med 44:790-7
Stokum, Jesse A; Gerzanich, Volodymyr; Simard, J Marc (2016) Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab 36:513-38
Hosier, Hillary; Peterson, David; Tsymbalyuk, Orest et al. (2015) A Direct Comparison of Three Clinically Relevant Treatments in a Rat Model of Cervical Spinal Cord Injury. J Neurotrauma 32:1633-44
Kunte, Hagen; Farhadi, H Francis; Sheth, Kevin N et al. (2015) Sulfonylureas--a novel treatment to reduce tissue damage after acute spinal cord injury? Lancet Neurol 14:352
Karimy, Jason K; Kahle, Kristopher T; Kurland, David B et al. (2015) A novel method to study cerebrospinal fluid dynamics in rats. J Neurosci Methods 241:78-84

Showing the most recent 10 out of 28 publications