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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