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A2-03
THE ROLE OF 7,8-DIHYDROXYFLAVONE IN PREVENTING
DENDRITE DEGENERATION IN CORTEX AFTER MODER-
ATE TRAUMATIC BRAIN INJURY
Shu Zhao
1,4
, Xiang Gao
1
, Jinhui Chen
1
, Weiren Dong
4
1
Indiana University School of Medicine, Neurosurgery, Indianapolis,
USA
2
Indiana University School of Medicine, Stark Neuroscience Research
Institute, Indianapolis, USA
3
Indiana University School of Medicine, Spinal Cord and Brain Injury
Research Group, Indianapolis, USA
4
Southern Medical University, Department of Histology and Embry-
ology, GuangZhou, China
Traumatic brain injury (TBI) is a serious public health problem in the
United States (US). TBI is a contributing factor to a third (30.5%) of all
injury-related deaths in the US. Every year, at least 1.7 million TBIs
occur either as an isolated injury or along with other injuries. In 2010, the
total of direct and indirect medical costs was an estimated $80 billion.
Our previous research showed that traumatic brain injury (TBI) induced
by controlled cortical impact (CCI) causes not only massive cell death,
but also results extensive dendrite degeneration in those spared neurons
in the cortex. Cell death and dendrite degeneration in the cortex may
contribute to persistent cognitive, sensory, and motor dysfunction. There
is still no approach available to prevent cells from death and dendrites
from degeneration following TBI. When we treated the animals with a
small molecule, 7,8-Dihydroxyflavone (DHF) that mimics the function
of BDNF through provoking TrkB activation, reduced dendrite swellings
in the cortex. DHF treatment also prevented dendritic spine loss after
TBI. Functional analysis showed that DHF improved rotarod perfor-
mance on the third day after surgery. These results suggest that DHF
treatment significantly prevented dendrites from degenerating, and pro-
tected dendritic spines against TBI insult. Consequently, DHF can par-
tially improve the behavior outcomes after TBI.
Keywords: Traumatic brain injury, dendrite, degeneration, brain-
derived neurotrophic factor, 7,8-dihydroxyflavone
A2-04
PROFILE OF PHOSPHOLIPID ALTERATIONS OF SPINAL
CORD INJURY: LIPIDOMIC ANALYSIS
Nai-Kui Liu
1
, Ling-Xiao Deng
1
, Miao Wang
2
, Qing-Bo Lu
1
, Xiang-
Bin Wu
1
, Chunyan Wang
2
, Xianlin Han
2
, Xiao-Ming Xu
1
1
Indiana University School of Medicine, Neurological Surgery, In-
dianapolis, USA
2
Sanford-Burnham Medical Research Institute, SBMRI, Orlando, USA
Although phospholipid alteration has long been associated with spinal
cord injury (SCI), its profile and specific role in mediating damage is
not well understood. In this study, we investigated alteration of phos-
pholipids with an emphasis on cardiolipin (CL), in the adult rat spinal
cord following a T10 contusive injury using an IH impactor (175
kdyne). Mass spectrometry-based lipidomic analysis showed a signifi-
cant decrease in CL, sulfatide, phosphatidylinositol and phosphatidyl-
choline as well as a significant increase in lyso-cardiolipin (lyso-CL),
lyso-phosphatidylcholine and acylcarnitine after SCI. CL is emerging as
an important player in the control of the mitochondrial phase of apo-
ptosis. The content of CL was found to be significantly reduced at 3 and
24 h after SCI while lyso-CL was increased only at 24 h after the injury.
Over 50 distinct CL molecular species were readily identified. Of them,
50% were significantly reduced after SCI. These reduced CL species
mainly contain polyunsaturated arachidonic acid (C
20:4
)(AA), doc-
osahexaenoic acid (C
22:6
)(DHA), and linoleic acid (C
18:2
)(LA) fatty
acids that are highly susceptible to peroxidation. Additionally, 4-HNE,
a marker of lipid peroxidation, also increased at 3 and 24 h after SCI.
These findings suggest that CL underwent oxidation and hydrolysis
after SCI.
In vitro
experiments showed that cytosolic phospholipase A
2
(cPLA
2
) activation induced CL loss.
In vivo
experiments showed that
mitochondrial cPLA
2
activation was increased after SCI. Remarkably,
blocking cPLA
2
pharmacologically with AACOCF3 in rats or genetic
deletion of cPLA
2
in mice reduced CL loss, mitochondrial dysfunction,
cytochrome c release, and neural apoptosis after SCI. These findings
collectively suggest that CL alteration is an early response following
SCI and that such CL alteration is mediated by oxidative stress and
cPLA
2
activation. Thus, CL alteration may play an important role in the
pathogenesis of SCI, and as such could be an attractive therapeutic
target for ameliorating secondary SCI.
Keywords: spinal cord injury, cardiolipin, cPLA2, apoptosis
A2-05
DOES THE PLASMINOGEN ACTIVATION SYSTEM REG-
ULATE POST-TRAUMATIC DEMENTIA?
Maithili Sashindranath
1,2
, Andre Samson
1,2
, Anna Tja¨rnlund-Wolf
4
,
Maria Daglas
1,2
, Adam Galle
1,2
, Amanda Au
1,2
, Dominik Draxler
1,2
,
Shiji Varghese
3
, Qiao-Xin Li
3
, Colin Masters
3
, Robert Medcalf
1,2
1
Monash University, Australian centre for blood diseases, Melbourne,
Australia
2
Monash University, Molecular Neurotrauma and Haemostasis,
Melbourne, Australia
3
Florey Institute of Neuroscience and Mental Health, University of
Melbourne, Melbourne, Australia
4
Institute of Neuroscience and Physiology, Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden
Young adults with a medical history of moderate to severe brain
trauma have an increased risk of developing Alzheimer disease
(AD), Lewy body disease- like pathology and Chronic traumatic
encephalopathy (CTE). The plasminogen activating (PA) system
facilitates breakdown of blood clots in the circulation, but also
regulates extracellular activities in the brain. tPA is a protease that
cleaves plasminogen to generate plasmin, which facilitates clot re-
moval. tPA activity is down-regulated by
a
-synuclein, a protein that
accumulates in Lewy bodies. Clearance of exogenous A
b
is signif-
icantly slower in mice lacking tPA or plasminogen, confirming that
the tPA–plasmin system is involved in A
b
degradation. We have
previously shown that plasmin deficiency leads to enhanced accu-
mulation of aggregated tubulin after trauma. We investigated whe-
ther plasmin deficient mice are more susceptible to accumulation of
amyloid-
b
leading to dementia-related pathology with 24–72h post-
trauma. Our data shows that deficiency of plasmin does not result in
an increased post-traumatic accumulation amyloid-
b
within this
timeframe and does not promote cognitive dysfunction over a lon-
ger-term period. We quantitated amyloid-
b
, Tau and
a
-synuclein in
post-mortem brain tissue of TBI and non-TBI patients. We found an
increase in amyloid-
b
as well as oligomeric
a
-synuclein within one-
week post-TBI. Preliminary analysis shows that amyloid burden was
increased in patients who had the 7351C/T polymorphism in the tPA
gene, that results in a decrease in tPA activity. Therefore the PA
system may have a role in regulating the onset of dementia-like
pathology after trauma. However it is likely that tPA-mediated
clearance of aggregated proteins may occur via plasminogen-
dependent and independent mechanisms.
Keywords: plasminogen activation system, amyloid beta, alpha
synuclein, tissue plasminogen activator
A-20