162 / 198
Conclusions:
fNIRS combined with hypercapnia challenge or
cognitive testing are practical, noninvasive methods to assess vascular
function after TBI and are both less expensive and more portable
than MRI-based technologies. These results support the use of both
fNIRS methods as biomarkers for clinical trials of vascular-directed
therapies.
Keywords: Near InfraRed Spectroscopy, cerebrovascular reactivity,
hypercapnia challenge, functional NIRS testing
D9-09
HEME OXYGENASE-1 AND LIPOCALIN-2 INTERACTION
DURING HEME PROCESSING AFTER TRAUMATIC BRAIN
INJURY
Nicholas Russell
, Linda Phillips
Virginia Commonwealth University, Department of Anatomy and
Neurobiology, Richmond, USA
Heme Oxygenase-1 (HO-1), the inducible form of Heme Oxygenase,
degrades heme into biliverdin, CO, and iron. It is a heat shock protein,
robustly induced by CNS vascular hemorrhage following traumatic
brain injury (TBI). Notably, HO-1 activity releases highly oxidative
iron, which can promote local pathology, as well as up-regulate
transcription to buffer acute free radical damage, and potentially af-
fect neural plasticity during postinjury recovery. HO-1 production is
partially self-regulated via induction of Nrf2 signaling; Nrf2 is a
transcription factor that activates the consensus antioxidant response
element targeting numerous antioxidant genes. We hypothesized that
time dependent HO-1/NRf2 axis activation post-TBI mediates iron
processing pathways to influence tissue recovery. Using rat central
fluid percussion TBI, post-injury HO-1 protein expression in hippo-
campus (HC) and cortex (CTX) was compared with downstream
biliverdin/bilirubin deposition and level of iron transport protein li-
pocalin-2 (LCN2). Western blot (WB) analysis demonstrated that HO-
1 protein peaks 3d post-injury and persists until 7d in HC and CTX.
CTX HO-1 is differentially distributed over post-injury time, initially
found in GFAP
+
astrocytes, then increasingly expressed by IBA1
+
cells localized at necrotic sites and around small vessels. A 3d peak in
HO-1 expression is consistent with the documented time course of
heme release/degradation after brain injury. Interestingly, HC also
exhibits a similar HO-1 protein expression profile without overt
hemorrhage. Optical analysis shows sequential evolution of biliverdin
and bilirubin deposition in the CTX through 7d. Paired Perls stain
revealed cellular iron deposition by 3d, indicating onset of significant
heme degradation. Further, WB analysis shows high LCN2 expression
immediately post-injury, peaking at 1d and declining at 3d and 7d.
Preliminary microarray gene profiling supports HO-1 transcript ele-
vation at 1d and 7d; also transient acute mRNA increase in LCN2 at
1d post-injury. Overall, our results reveal time dependent HO-1 ac-
tivation and potential interaction with LCN2 to mediate heme/iron
processing following TBI. The data also suggests that delay in post-
injury heme accumulation/breakdown, along with ongoing elevation
of heme lytic products and iron transporters, may expand the thera-
peutic window for post-injury buffering of hemorrhage-induced pa-
thology. Support: NIH-NS056247/NS057758.
Keywords: Heme Oxygenase 1, Lipocalin 2, Iron Metabolism,
Heme Metabolism
D9-10
AXONAL INJURY AND NEUROBEHAVIORAL IMPAIR-
MENT AFTER SUBARACHNOID HEMORRHAGE
Terrance Kummer
1
, Joong Hee Kim
1
, Joey Benetatos
1
, Eric Milner
2
,
Gregory Zipfel
2
, David Brody
1
1
Washington University School of Medicine, Neurology, Saint Louis,
USA
2
Washington University School of Medicine, Neurosurgery, Saint
Louis, USA
The great majority of acute brain injury results from trauma or from
disorders of the cerebrovasculature. Although traumatic and vascular
brain injuries are generally considered separately, brain hemorrhage
shares many physiological parallels with trauma, and both result in
debilitating chronic neurocognitive deficits. Aneurysmal subarachnoid
hemorrhage (SAH) is the most devastating variant of hemorrhagic
brain injury, carrying a 1-month mortality rate of nearly 50%. The
underlying causes of neurocognitive deficits in SAH are unknown and
invisible to clinical imaging modalities. We recently found that SAH
induces radiological and pathological axonal injury similar to that
seen after trauma. We therefore sought to develop a mouse model of
SAH-induced neurobehavioral deficits to determine whether axonal
injury is a key correlate of long-term neurobehavioral sequelae in
SAH, as it is following trauma. We developed a SAH induction and
post-SAH screening protocol that yields multi-domain neurobeha-
vioral deficits in memory and cognition (Morris Water Maze test),
depression- and anxiety-related behaviors (tail suspension and ele-
vated plus maze tests), and in social behavior (social interaction test).
These impairments parallel those reported by patients after brain
hemorrhage and trauma. We furthermore developed an advanced
diffusion MRI approach involving diffusion kurtosis and generalized
q-sampling imaging with paired histological analysis to define ra-
diological biomarkers of acute brain injury pathways following SAH,
and to correlate these biomarkers with neurobehavioral outcomes. Our
results demonstrate that post-hemorrhagic neurobehavioral outcomes
can be analyzed in a highly tractable model organism, and lay the
groundwork for mechanistic analysis of these outcomes using clinically
translatable radiological biomarkers. These findings and approaches
are likely to have application to post-traumatic neurocognitive deficits
as well.
Keywords: subarachnoid hemorrhage, MRI, diffusion tensor im-
aging, behavior
A-126