Page 143 - NNS 2014 Program & Abstract Book

2UCLA Brain Injury Research Center, Los Angeles, USA
3University of California Los Angeles, Dept. Integrative Biology and
Physiology, Los Angeles, USA
The brain is a highly metabolic organ, such that disruptions of met-
abolic homeostasis can have dramatic consequences for cognitive
function. TBI is followed by a state of metabolic dysfunction, com-
promising the capacity of neurons to sustain brain plasticity. There is
a paucity of studies showing how metabolic adaptations support
neuronal resilience crucial for coping with the effects of TBI. We
have examined the capacity of a flavonoid derivative 7,8-dihydroxy-
flavone (7,8-DHF), a TrkB agonist that crosses the blood brain barrier,
to improve brain metabolism and plasticity in animals subjected to
fluid percussion injury (FPI). The 7,8-DHF (5 mg/kg, ip) was ad-
ministered daily for 7 days until behavioral assessment. TBI resulted
in metabolic disturbances, as evidenced by alterations in energy ho-
meostasis markers (AMPK phosphorylation and SIRT1 levels) and
mitochondrial biogenesis (levels of PGC-1a and TFAM). These
changes were concurrent with reductions in memory function assessed
with Barnes maze. Treatment with 7,8-DHF ameliorated impairments
in cognitive function and energy homeostasis. 7,8-DHF also enhanced
the activation of TrkB and downstream signaling such as CREB. In
vitro studies showed that 7,8-DHF (200 and 400 nM) upregulates the
levels of biogenesis activator PGC-1a, and CREB phosphorylation in
N2a-neuroblastoma cells, suggesting that activation of BDNF-TrkB
signaling is pivotal for synaptic plasticity and energy metabolism. The
treatment with 7,8-DHF (200 nM) also elevated the mitochondrial
respiratory capacity, measured by Extracellular Flux analyzer, which
emphasizes the role of BDNF-TrkB signaling as mitochondrial bio-
energetics stimulator. This study highlights the action of BDNF-TrkB
signaling for building neuronal resilience underlying functional re-
covery following TBI. Results also suggest a close interplay between
mitochondrial function and synaptic plasticity in the mechanisms of
functional recovery after TBI (supported by NIH R01NS050465).
Key words
diet, functional recovery, metabolism, synaptic plasticity
D1-30
INTRACEREBROVENTRICULAR DELIVERY OF CHON-
DROITINASE ABC REDUCES POST-TRAUMATIC BRAIN
EDEMA IN MICE
Finan, J.D.1, Cho, F.S.1, Kernie, S.G.2, Morrison III, B.1
1Columbia University, Department of Biomedical Engineering, New
York, NY
2Columbia University Medical Center, Department of Pathology, New
York, NY
Edema remains a common and often lethal complication of severe
traumatic brain injury (TBI) with limited treatment options. We have
previously shown that chondroitin sulfate molecules in the tissue drive
edema and that chondroitinase ABC (ChABC) reduces edema by
breaking down these molecules. The goal of this study was to dem-
onstrate that intracerebroventricular delivery of ChABC reduces post-
traumatic brain edema in mice.
Controlled cortical impact was used to induce post-traumatic edema
on the left side of the brain in C57/BL6 mice. ChABC was delivered
into the right lateral ventricle through a needle inserted through the
skull under stereotactic guidance. After 24 hours, the mice were eu-
thanized and the brains removed. A 4mm thick coronal section of the
brain including the injury site was split into left and right hemispheres
and weighed. The samples were dried at 95 C for three days and
reweighed to determine the dry weight and water fraction.
Water fraction was significantly elevated above uninjured values on
the side ipsilateral to the injury but not on the contralateral side, indi-
cating that edema was confined primarily to the injured hemisphere.
ChABC treatment reduced water fraction on the side ipsilateral to the
injury from 79.1% (S.E. =0.087%) to 78.5% (S.E. = 0.13%). The cor-
responding water fraction in uninjured vehicle-treated animals was
78.1% (S.E. = 0.06%).
The treatment eliminated approximately half of the edema induced
by injury. This therapeutic strategy of delivering ChABC to the whole
brain through the ventricular space has significant translational po-
tential. Shunts are routinely placed in the ventricles of human patients
with severe TBI to drain cerebrospinal fluid. Such shunts provide a
convenient route of administration for this treatment. Future experi-
ments will describe the biochemical mechanism of this therapy in
more detail and reproduce these results in larger animals.
This work was supported by a Senior Fellowship in Biomedical
Science from the Charles H. Revson Foundation.
Key words
chondroitinase, intracerebroventricular, mouse model, therapy
D1-31
CCR2 DEFICIENCY IMPAIRS MACROPHAGE INFILTRA-
TION AND IMPROVES COGNITIVE FUNCTION AFTER
TRAUMATIC BRAIN INJURY
Hsieh, C.L.1,2, Niemi, E.C.1,2, Wang, S.H.1, Lee, C.1,2, Bingham, D.1,2,
Zhang, J.1,2, Charo, I.1, Huang, E.J.1,2, Liu, J.1,2, Nakamura, M.C.1,2
1University of California San Francisco, San Francisco, USA
2San Francisco VA Medical Center, San Francisco, USA
Traumatic brain injury (TBI) incites neuroinflammatory responses that
include a dramatic rise in macrophages in the brain. The mechanisms of
macrophage recruitment during TBI have not been defined. We deter-
mined the role of chemokine receptor, CCR2, in the macrophage re-
sponse to TBI using a model of controlled cortical impact. Leukocytes
were isolated from brain hemispheres of wild type and Ccr2-/- mice after
TBI and evaluated by flow cytometry. Ccr2-deficient mice showed a
90% reduction in macrophages in the ipsilateral hemisphere compared to
wild type animals one day after TBI, and an 80% reduction four days
after TBI. To determine the effects the CCR2-dependent response on
functional outcomes, Ccr2-/- and wild type mice were compared in be-
havioral tests beginning at three weeks after TBI. In open field tests, wild
type animals after TBI exhibited elevated hyperactivity levels compared
to sham controls. A lack of Ccr2 partially rescued hyperactivity levels. In
rotor rod testing, wild type animals after TBI showed reduced motor
functions. A lack of Ccr2 did not affect motor coordination on the rotor
rod. Importantly, while TBI induced significant impairments in memory
and learning in wild type mice as assessed by the Morris water maze
eight weeks after TBI, Ccr2-deficient mice demonstrated reduced im-
pairments in memory and learning. No difference in tissue loss was
detected between genotypes after TBI. However, Ccr2-/- mice after TBI
showed greater preservation of neuronal density in the hippocampus
compared to wild type mice after TBI, providing a possible explanation
for improved memory function. These data demonstrate that macrophage
recruitment to the brain following TBI is largely dependent on Ccr2 and
that lack of Ccr2 improves functional recovery. Therapeutic blockade of
CCR2-dependent responses may improve outcomes following TBI.
Key words
behavior studies, CCR2, flow cytometry, inflammation, macrophage,
traumatic brain injury
A-111