Page 142 - NNS 2014 Program & Abstract Book

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NEUREGULIN-1 INFUSION AFTER TBI IN ADOLESCENT
MICE IMPROVES COGNITIVE PERFORMANCE DURING
ADULTHOOD
Wu, L.1,2, Leung, W.1, Wang, X.1, Wu, J.2, Lo, E.H.1, Lok, J.1
1Massachusetts General Hospital, Boston, USA
2First Hospital of Jilin University, Changchun, China
Traumatic brain injury (TBI) is a leading cause of death and disability.
As adolescence is a pivotal period of normal brain function development,
brain trauma during adolescence often interferes with the normal ac-
quisition of cognitive skills, with impairments that may persist into
adulthood. Neuregulin-1 (NRG1) is an endogenous growth factor which
an epidermal growth factor (EGF)-like core domain (eNRG1) and is
involved in neuronal migration, axon pathway finding, myelination and
synaptogenesis. We studied the neuroprotective potential of NRG1-b in a
controlled cortical impact (CCI) model in mice equivalent to the ado-
lescent age group. 5-week-old C57BL6 mice were subjected to CCI. At
2 h after injury, the mice were given an intravenous injection of PBS or
NRG1-b, followed by a continuous infusion of PBS or NRG1-b deliv-
ered subcutaneously for 14 days with an Alzet pump. 5 months after CCI,
outcomes were evaluated - including motor function, cognitive function,
lesion volume, and axon integrity detected by immunohistochemistry.
Age-matched un-injured mice were used as normal controls. Post-trauma
treatment with NRG1-b did not result in a statistically significant change
in lesion volume or motor function in comparison to the PBS-treated
group. However, the NRG1-b treated mice had a statistically significant
improvement in the Morris Water Maze hidden platform trials, sug-
gesting that the NRG1-b infusion had a beneficial effect on spatial
learning and memory. Improved axon staining was also seen in brain
sections in NRG1-b treated mice compared to PBS-treated mice. Our
data suggest that NRG1-b has neuroprotective potential in the treatment
of TBI, and that its beneficial effects on the immature brain may lead to
long-term benefits during adulthood.
Key words
neuregulin-1, neuroprotection, pediatric, trauma
D1-27
MULTINEUROTROPHIN EXPRESSING FETAL CELL
TRANSPLANT IN PENETRATING BALLISTIC BRAIN IN-
JURY (PBBI)
Spurlock, M.S.1, Hosein, K.1, Bullock, M.R.1, Gajavelli, S.1,
Yokobori, S.1,3, O’Connell-Blaya, M.1, Leung, L.Y.2, Tortella, F.C.2
1University of Miami Miller School of Medicine, Miami, USA
2Center for Military Psychiatry and Neuroscience, Walter Reed Army
Institute of Research, Silver Spring, USA
3Department of Emergency and Critical Care Medicine, Nippon
Medical School, Tokyo, Japan
The purpose of this pilot study was to evaluate survival of genetically
modified fetal cell transplants in PBBI.
FDA approved naı¨ve human fetal spinal cord neural stem cells were
transplanted into Sprague Dawley (SD), Fischer344, or Athymic SD rats.
Male rats were subjected to PBBI and two weeks later allocated to:
Group1: no transplant, Group2: xenogeneic transplant. These groups were
immunosuppressed via tacrolimus, mycophenylate, and depo-medrol. In
Group 3, SD rat E14 cortical neural precursors lentivirally transduced to
express multineurotrophin (MNTS1) were transplanted into PBBI injured
SD rats. Group 3 was immunosuppressed with cyclosporine. Cells were
microinjected into the peri-lesion region (400,000/rat). The brains were
sectioned and assessed for cell specific markers for differentiation and
immune response. The human-to-rat transplant rejection at 1 week was
comparable to that in Fischer and Athymic at 4 weeks. All xenogeneic
transplants were rejected by 8 weeks. In the allogeneic rat-to-rat MNTS-1
expressing transplant group, a robust graft spanning a millimeter square
developed. Neurite lengths at week 1 were * 150 micron, and by week 8
extended 3 millimeters from the transplant to engraft the lesion. Var-
icosities suggestive of synaptic densities on neurites could be seen. Most
grafted cells labeled with neural markers while few labeled ambiguously
with glial markers. The pilot data indicates that the inflammation re-
sponse of PBBI and lack of sufficient growth factors mediate rejection of
transplanted naive stem cells. However, with appropriate growth factor
enhancement, allogeneic fetal transplants can survive and develop in the
PBBI model. Transduction of human cells with MNTS1 should allow for
their engraftment in athymic rats. These transplants can then be evaluated
for safety and therapeutic efficacy.
Key words
chronic TBI, stem cell
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SEQUENTIAL BETA-BLOCKER AND CELLULAR THERAPY
FOR TRAUMATIC BRAIN INJURY
Kota, D.J., Prabhakara, K.S., DiCarlo, B., Smith, P., Olson, S.D.
University of Texas Medical School at Houston, Houston, USA
More than 6.5 million patients are burdened by the physical, cognitive
and psychosocial deficits associated with traumatic brain injury (TBI)
in the US, accounting for $72 billion in direct and indirect costs. De-
spite extensive efforts to develop neuroprotective therapies for this
devastating disorder, there have been no successful outcomes in human
clinical trials to date. We hypothesized that due to the complexity of
TBI, there are multiple treatment windows in which different strategies
may be therapeutic. Retrospective studies have shown that beta-
adrenergic receptor blockers, specifically propranolol, significantly
decrease mortality of TBI, but increase complications associated with
inflammation. Conversely, cellular therapies have been shown to im-
prove long-term behavior following TBI, likely by reducing inflam-
mation. We hypothesized that a combination of acute propranolol and
delayed mesenchymal stem cells (MSC) would have additive effects in
treating a rodent model of severe TBI. We have found that the com-
bined treatments are well tolerated with no adverse events, they display
cumulative effects in decreasing BBB permeability at 96 hrs after in-
jury, and they alter the number, activation, and localization of microglia
7 days after injury. Ongoing studies seek to optimize dosing and de-
livery, explore long-term cognitive outcome, and ultimately determine
if this combinatorial therapy could be applied to increase clinical effi-
cacy compared to the individual treatments alone.
Key words
combination therapy, mesenchymal stem cells, propranolol, TBI
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ACTIVATION OF BDNF-TRKB SIGNALING RECRUITS ME-
TABOLIC SIGNALS TO IMPROVE FUNCTIONAL RE-
COVERY FOLLOWING BRAIN TRAUMA
Agrawal, R.3, Ying, Z.3, Gomez-Pinilla, F.1–3
1University of California Los Angeles, Dept. of Neurosurgery, Los
Angeles, USA
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