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putational models of axon biomechanics have been developed and are
used in conjunction with the present model to complete the linkage of
external loading conditions to neurological outcomes. The present
model can be used as a platform to study trauma-induced alterations in
axonal functionality, mechanisms of axonal resilience to trauma and
axon healing and recovery.
Keywords: mTBI, paranode demyelination, potassium, swelling,
concussion, repetitive injury
B3-03
THE MICROTUBULE-STABILIZING DRUG EPOTHILONE D
INCREASES AXONAL SPROUTING RESPONSE IN AN IN
VITRO MODEL OF TRANSECTION INJURY
Mariana Brizuela
, Jyoti A. Chuckowree, Catherine A. Blizzard,
Kaylene M Young, Tracey C Dickson
Menzies Institute for Medical research University of Tasmania, UTAS,
Hobart, Australia
The loss and misalignment of microtubules are considered a hallmark
feature of the degeneration that occurs after Traumatic Brain Injury
(TBI). Therefore, microtubule-stabilizing drugs are attractive as potential
therapeutics for use following TBI. Taxol, a widely used anti-cancer
drug, has shown promising outcomes in the treatment of various animal
models of neural trauma, however, Taxol is not ideal for TBI treatment
due to its limited blood-brain barrier (BBB) permeability. Epothilone D
(EpoD), another microtubule-stabilizing drug, can penetrate the BBB and
hence may be more therapeutically appropriate. We have characterized
the effects of EpoD on the post-injury axonal sprouting response of
relatively mature cortical neurons in an
in vitro
model of CNS trauma.
The number of tau labeled axonal sprouts traversing the injury site was
significantly reduced (
p
<
0.05) by 100 nM of EpoD and significantly
increased (
p
<
0.01) by 0.1 nM of the drug. Furthermore we found no
differences between EpoD and vehicle treated axons with regards to their
mean and maximal sprout outgrowth velocity, indicating that EpoD ef-
fects the number of axons that sprout but not their net growth. To de-
termine whether this effect was specific to pyramidal neurons, we applied
EpoD to cortical neuron cultures derived from Thy1-YFP mice. Low
doses of EpoD significantly increased the number of YFP-positive axons
that sprouted into the injury site when compared to vehicle treated cul-
tures (
p
<
0.05). Our investigations demonstrate that primary cortical
neurons can tolerate relatively high concentrations of EpoD, and im-
portantly that EpoD significantly increases the regenerative response of
pyramidal axons in a dose dependent manner. These data suggest that
EpoD may be a potent therapeutic for enhancing brain repair following
TBI and further studies in our laboratory will aim to characterize the
effects of Epo D in an
in vivo
model of trauma using the lateral fluid
percussion injury model in adult mice.
Keywords: Microtubule stabilising drugs, Epothilone D, axonal
sprouting, Primary neuronal culture
B3-04
DTI CORRELATES OF ATTENTION AND PROCESSING
SPEED IN SUB-ACUTE AND CHRONICTRAUMATIC BRAIN
INJURY
Shannon McNally
1
, Katherine Lopez
2
, Dzung Pham
2
, Yi-Yu Chou
2
,
John Dsurney
2
, Leighton Chan
1,2
1
National Institutes of Health, Clinical Center, Bethesda, USA
2
Center for Neuroscience and Regenerative Medicine, Phenotyping
Core, Rockville, USA
Introduction:
Diffusion Tensor Imaging (DTI) has allowed investi-
gators to more thoroughly evaluate the effects of traumatic brain in-
jury (TBI). Using DTI, some investigators have been able to establish
associations between various brain structures and specific cognitive
tasks in chronic TBI (Kraus et al. 2007). We examined the relation-
ship between measures of white matter integrity and performance on
standardized neuropsychological tests measuring attention and pro-
cessing speed in patients who had sustained a TBI at both the sub-
acute and chronic phases.
Methods:
Twenty three TBI patients (mean age: 42.1 years) cate-
gorized as mild, (n
=
5) moderate (n
=
15), and severe (n
=
3) were
evaluated within 90 days and at one year post-injury. At both time
points, a 3-Tesla MRI scan was performed, as well as battery of
neuropsychological tests. Using the SINAPS software package that
includes motion and distortion correction, mean fractional anisotropy
(FA), mean diffusivity (MD), axial diffusivity (AD), and radial dif-
fusivity (RD) were calculated for regions implicated in attention and
processing speed.
Results:
At the 90 day mark, processing speed correlated positively
with FA in the genu of the corpus callosum (CC) (r
=
.56, p
<
.007)
whereas RD in the CC body was negatively correlated (r
= -
.528,
p
=
.01). Measures of attention were associated with FA in the right
inferior fronto-occipital fasciculus (r
=
.83, p
=
.003) and AD in the
fornix (r
=
.536, p
=
.008).
At one year post-injury, tests of attention positively correlated with
FA in the left anterior thalamic radiation. A greater number of regions
were related to processing speed; FA in the left inferior fronto-
occiptal fasciculus showed a positive correlation (r
=
.550, p
=
.008).
RD and MD in the CC posterior and the fornix were also highly
correlated.
Conclusions:
These results support the hypothesis that higher FA
and lower RD in various axonal bundles are associated with better
performance in neuropsychological tests of attention and processing
speed.
Keywords: Diffusion Tensor Imaging, Neuropsychology, Attention,
Traumatic Brain Injury
B3-05
THERAPEUTIC EFFECTS OF TAMOXIFEN IN SPINAL
CORD INJURY
Caleb Smith
1
, Jutatip Guptarak
2
, Russell Lolley
1
, Peter Fitzgibbons
1
,
Alexander Mackay
1
, Stephen Mulkey
1
, Harriet Barratt
1
, Tabibian
Borna
1
, Hailey Budnick
1
, Ricardo Parra
1
, Olivera Nesic-Taylor
1,2
1
Texas Tech University Paul L. Foster School of Medicine, Depart-
ment of Medical Education, El Paso, USA
2
University of Texas Medical Branch Galveston, Department of Bio-
chemistry and Molecular Biology, Galveston, USA
Tamoxifen (TMX) is a breast cancer medication as it acts as a se-
lective estrogen receptor modulator that can mimic the neuroprotec-
tive effects of estrogen, but lacks its systemic side effects. We found
that TMX significantly improved the motor recovery of partially
paralyzed hind limbs of male adult rats with thoracic spinal cord
injury (SCI), thus indicating a translational potential for this cancer
medication, given its clinical safety and applicability. To shed light on
the mechanisms underlying the beneficial effects of TMX for SCI, we
used proteomic analyses, Western blots and histological assays, which
showed that TMX treatment spared mature
oligodendrocytes
increased myelin levels and altered reactive
astrocytes
, including
the upregulation of the water channels aquaporin 4 (AQP4). AQP4
increases in TMX-treated SCI rats were associated with smaller
A-51