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response compared to WBI or CCI alone. Sustained increases in IP-10

and Rantes might facilitate recruitment of macrophages/microglia in

striatum after combined injury. Defining the mechanisms underlying

damage from secondary insults could be vital to development of ra-

diation mitigators.

Support: U19-AI068021, NS061817, NS076511.

Keywords: Multiplex

C7-13

NOCICEPTIVE STIMULATION INDUCES CASPASE 1 AC-

TIVATION FOLLOWING SPINAL CORD INJURY

Joel Turtle

1

, Misty Strain

1

, Joshua Reynolds

1

, Yung-Jen Huang

1

,

Sandra Garraway

2

, James Grau

1

1

Texas A&M University, Institute for Neuroscience, Bryan, USA

2

Emory University School of Medicine, Department of Physiology,

Atlanta, GA

Processes that unfold within the first 48 hours of spinal cord injury

(SCI) modulate cell death and determine, to a large extent, long-term

prognosis. We have shown that nociceptive signals can influence these

processes and the development of secondary damage. Based on

studies from a transection model, we hypothesize that nociceptive

input after injury undermines cell survival, impairs recovery of lo-

comotor function, and promotes neuropathic pain. However, the

mechanism of impaired recovery following nociceptive input is rel-

atively unknown. Here, we used two different models of nociceptive

stimulation (uncontrollable electrical stimulation to the tail or intra-

dermal capsaicin injection to a hind paw) to explore the mechanism of

impaired recovery following spinal cord injury. We examined loco-

motor recovery following injury as well as the underlying cellular

mechanisms using immunoblotting of the lesion site. Either intra-

dermal capsaicin injection or uncontrollable tail shock significantly

impaired locomotor recovery for at least 28 days when given 24 hours

after injury. In addition, nociceptive input increased protein expression

of active caspase 1 compared to control subjects. Further, subjects re-

ceiving capsaicin or shock treatment showed increased processing of

the pro-inflammatory cytokines IL-1beta and IL-18. These data suggest

that after spinal cord injury, nociceptive stimulation promotes the ac-

tivation of an inflammasome and leads to caspase 1 activation, in-

flammatory cytokine processing, and potentially pyroptotic cell death.

Future work is examining the cell types responsible for inflammasome

activation, other mechanisms of cell death, and potential pharmaco-

logic targets that may reverse this effect. [Supported by Neilson

Foundation and Mission Connect grants to JG]

Keywords: pyroptosis, pain, spinal cord injury, inflammation

C7-14

TIBIAL FRACTURE EXACERBATES TRAUMATIC BRAIN

INJURY OUTCOMES AND INFLAMMATION IN A MOUSE

MODEL OF MULTI-TRAUMA

Sandy Shultz

1

, Mujun Sun

1

, David Wright

1

, Rhys Brady

2

, Shijie Liu

1

,

Sinead Beynon

1

, Shannon Schmidt

2

, Terence O’Brien

1

, Stuart

McDonald

2

1

The University of Melbourne, Medicine, Parkville, Australia

2

La Trobe University, Human Biosciences, Melbourne, Australia

Multi-trauma is a common medical problem worldwide, and often

involves concurrent traumatic brain injury (TBI) and bone fracture.

Despite the high incidence of combined TBI and fracture, pre-clinical

TBI research commonly employs independent injury models that fail

to incorporate the pathophysiological interactions occurring in multi-

trauma. Here we developed a novel mouse model of multi-trauma, and

investigated whether bone fracture worsened TBI outcomes. Male

mice were assigned into four groups: sham-TBI

+

sham-fracture

(SHAM); sham-TBI

+

fracture (FX); TBI

+

sham-fracture (TBI); and

TBI

+

fracture (MULTI). The injury methods included a closed-skull

weight-drop TBI model and a closed tibial fracture. After a 35-day

recovery, mice underwent behavioral testing and MRI. MULTI mice

displayed abnormal behaviors in the open-field compared to all other

groups. On MRI MULTI mice had enlarged ventricles and diffusion

abnormalities compared to all other groups. These changes occurred

in the presence of heightened neuroinflammation in MULTI mice

at 24 h and 35 days post-injury, and elevated edema and blood-

brain-barrier disruption at 24 h post-injury. Together these findings

indicate that tibial fracture worsens TBI outcomes, and that exacer-

bated neuroinflammation may be an important factor that contributes

to these effects, which warrants further investigation.

Keywords: Multi-trauma, Polytrauma, Animal model, Inflamma-

tion, MRI, DTI

C7-15

NADPH OXIDASE 4 INHIBITION REVERSES IRON IN-

DUCED PERTURBATIONS OF REACTIVE OXYGEN SPE-

CIES WITHIN ACTIVATED MICROGLIA

Young Yauger

1

, Sara Bermudez

2

, Kimberly Byrnes

1,2

1

Uniformed Services University, Neuroscience Program, Bethesda,

USA

2

Uniformed Services University, Department of Anatomy, Physiology

and Genetics, Bethesda, USA

Iron is an essential element for cellular homeostasis. It facilitates

molecular rearrangement that aids in ATP creation, myelin synthesis,

and a myriad of enzymatic reactions. Recently, iron accumulations

within the brain have been associated with pro-inflammatory disease

states, such as Parkinson’s or Alzheimer’s. There are similarities be-

tween the inflammatory cascade of these diseases and traumatic brain

injury (TBI). Since microglia are the primary mediators of inflam-

mation within the brain parenchyma, we hypothesized that excessive

iron can exacerbate the microglia inflammatory response by accen-

tuating activity of NADPH oxidase 4 (NOX4), a known reactive ox-

ygen species (ROS) synthesizer. Utilizing the BV2 microglial cell

line, we evaluated the effect of iron sulfate (FeSO

4

) on microglial

related inflammation and NOX4. BV2 cells were cultured with lipo-

polysaccharide (LPS) prior to addition of FeSO

4

for 24 hours prior to

evaluation of ROS, cell death, and nitric oxide (NO) release. Iron

alone had no effect on any outcome measure in microglia. However,

ROS production was significantly elevated by FeSO

4

in a dose-

dependent manner when cells were pre-stimulated with LPS. Neither

FeSO

4

nor LPS induced significant changes in cell death. Finally,

assessment of NO showed a robust response of the BV2s with LPS

treatment (p

<

0.001), however no difference existed between the LPS

exposed group and those groups with FeSO

4

and LPS. In order to

determine the mechanism of FeSO

4

perturbations, we used the NOX4

specific inhibitor, GKT137831. GKT137831 reduced the production

of ROS in both LPS and LPS

+

FeSO

4

treated microglia to control

levels. These results now show that FeSO

4

increases ROS expression

in activated microglia, and suggest that iron induced ROS expression

in microglia may depend on NOX4 activation. Elevated ROS can play

a role in inducing inflammation and neuronal apoptosis; our data now

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