NNS 2015 Program & Abstract Book

S11-04

TARGETING THE TRPV4 CHANNEL TO REDUCE IN-

FLAMMATION AND IMPROVE OUTCOME FOLLOWING SCI

Raymond Grill

University of Mississippi Medical Center, Department of Neurobiol-

ogy and Anatomical Sciences, Jackson, USA

Trauma to the spinal cord elicits a profound inflammatory response

both within the damaged cord as well as throughout the rest of the

body. This inflammatory response is further characterized by the ac-

tivation and mobilization of systemic as well as CNS immune com-

ponents that are thought to provide both beneficial as well as

pathological aspects to the healing process. Mechanisms underlying

the activation and progression of this immune/inflammatory activation

continue to be unveiled. The Transient Receptor Potential channel,

subfamily V, member 4 (TRPV4) is a calcium-permeable, non-

selective cation channel expressed throughout the body and serves as

a molecular and mechanical sensor to detect alterations in tempera-

ture, osmolality blood pressure, etc. Due to TRPV4’s association with

endothelial cells and role as regulator of vascular tone, we hypothe-

sized that aberrant activation of TRPV4 via mechanical insult may

worsen spinal vascular leakage produced by contusion injury. We

determined that blood-spinal cord-barrier (BSCB) breakdown was

reduced in TRPV4-null mice compared to wild type (WT) when as-

sessed 48 hours post-spinal contusion injury. Utilizing additional

mutant mice in which TRPV4 is linked to GFP, we observed strong

co-association of GFP with both spinal microglia as well as splenic

macrophages. This lead us to hypothesize that TRPV4 activation

following spinal cord injury (SCI) may contribute to systemic immune

activation/inflammation following SCI. WT mice were treated with

the selective TRPV4 inhibitor, HC-067047, once daily (10 mg/kg) for

three days. We observed that HC-067047 treatment lead to a signifi-

cant reduction in both microglial and astrocytic activation at the lesion

site compared to vehicle-treated controls. In addition, HC-067047-

treatment significantly attenuated the loss in splenic mass normally

observed following CNS trauma. Our results suggest that trpV4 in-

hibition may attenuate both spinal and systemic immune activation/

inflammation following SCI.

Support provided by: 1) Mission Connect, a Project of the TIRR

Foundation, and 2) The Gillson-Longenbaugh Foundation

Keywords: blood spinal cord barrier, spleen, neuroimmune, trpv4,

macrophages

S11-05

ATTENUATING GASTROINTESTINAL VASCULAR PER-

MEABILITY AFTER SPINAL CORD INJURY

Juan Herrera

, Kurt Bockhorst

, Karen Uray

, Raymond Grill

Ponnada Narayana

UTHealth Medical School at Houston, Diagnostic and Interventional

Imaging, Houston, USA

UTHealth Medical School at Houston, Pediatric Surgery, Houston,

USA

University of Mississippi Medical Center, Neurobiology and Anato-

mical Sciences, Jackson, USA

Gastrointestinal (GI) hemorrhage is a dangerous complication after

spinal cord injury (SCI). Undiagnosed abdominal complications are the

third leading cause of death in paraplegic and quadriplegic patients after

the acute phase of injury. The main objectives of this study is to in-

vestigate the compromise of the GI vascular permeability in mice

during the acute phase of injury and to determine if this compromise

can be attenuated by an intravenous (IV) administration of angiopoietin-

1 (Ang-1). Ang-1 is a vascular stabilizing protein expressed constitu-

tively by endothelial cells, pericytes, astrocytes, smooth muscle cells,

and fibroblasts. The study examined GI vasculature permeability using

dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)

48 hours after a spinal contusion injury. The contusion injury was de-

livered using the Infinite Horizon Impactor (60 kDynes with a 1 second

dwell time) at thoracic level 8. Treatments groups received a single IV

administration of Ang-1 (30

g, 100

g, or 300

g) through the jugular

vein three hours following injury. Controls groups received an IV ad-

ministration of saline. DCE-MRI analysis indicated that there is a sig-

nificant increase in GI vascular permeability in injured animals

compared to uninjured animals at 48 hours after injury. We observed a

significant decrease in GI vascular permeability following a single IV

injection of Ang-1 (300

g) compared to saline treated animals. In

addition, Ang-1 treatment produced a qualitative improvement in GI

morphological outcome. SCI produced disruption in GI villi compared

to naive, uninjured control mice in H&E stained GI tract sections. Ang-

1 (300

g) treated animals exhibited reduced GI villi damage compared

to vehicle-treated subjects. Taken together the data suggests that pro-

moting vascular stability following SCI by an IV administration of Ang-

1 not only reduces GI vascular permeability but also appears to preserve

intestinal villi.

Keywords: gastrointestinal, dynamic contrast enhanced imaging,

vascular permeability

S12 Open Communication: Clinical

S12-01

A PROGNOSTIC MODEL FOR DETERMINING ONE-

MONTH OUTCOMES IN MILD TRAUMATIC BRAIN INJURY

Hayley Falk

, HeadSMART Investigators

Johns Hopkins University School of Medicine, Emergency Medicine,

Baltimore, USA

There are currently no tools for aiding emergency physicians in edu-

cating mild traumatic brain injury (mTBI) patients regarding the

prognosis of their injury. We sought to derive a model for identifying

mTBI patients at risk for incomplete recovery from their symptoms at

1-month after injury. We analyzed data from a prospective cohort of

TBI patients presenting to an urban emergency department (ED) (The

Head

injury

erum

arkers for

ssessing

esponse to

rauma

[HeadSMART] cohort). Subjects presenting within 24 hours of injury

were interviewed on the day of injury. Telephone interviews were

performed at 1-month after injury to determine TBI outcomes. In-

complete recovery was defined as Glasgow Outcome Scale Extended

(GOSE)

8. Prognostic models were built using univariable and mul-

tivariable logistic regression methods and stepwise selection proce-

dures. A total of 194 subjects were enrolled between April 2014 and

February 2015. Of this number, 108 were mTBI patients with a pre-

senting Glasgow Coma Scale (GCS) of 14 or 15; a negative head CT

scan; and 1-month follow-up data were included in this analysis. Within

this subpopulation, 52.8% (57/108) had GOSE

8 at 1 month. Predictor

variables included in the final prognostic model were altered mental

status at presentation (AMS), gender, race (African-American or non-

African American), work-related injury, dangerous injury mechanism

(ejection from motor vehicle, pedestrian struck, fall from height

3ft or

5 stairs), and other injury (solid organ injury or bony fracture). This

model discriminated between subjects with and without incomplete

recovery with an area under the receiver operator curve (AUC) of

0.82 (95% CI: 0.73 – 0.88). A HeadSMART30 score was computed

by assigning a score of 2 for AMS, 1 for female gender, 2 for

A-13