Page 112 - NNS 2014 Program & Abstract Book

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NEUROPROTECTIVE EFFECTS OF LEVETIRACETAM RE-
QUIRES EXTENDED TREATMENT IN A RAT MODEL OF
PENETRATING BALLISTIC-LIKE BRAIN INJURY
Caudle, K.L., Shear, D.A., Pedersen, R., Sun, J., Flerlage, W., Faden,
J., Mountney, A., Schmid, K.E., Tortella, F.C., Lu, X.C.
Walter Reed Army Institute of Research, Silver Spring, MD
Levetiracetam (Keppra) is a FDA approved anti-epileptic drug that
has demonstrated neuroprotective effects in animal models of trau-
matic brain injury (TBI). Recently we demonstrated its anti-seizure
effects on attenuating nonconvulsive seizures (NCS) induced by
penetrating-ballistic-like brain injury (PBBI) in rats. The purpose of
the current study was to determine whether a comparable treat-
ment regimen would improve motor and cognitive function fol-
lowing PBBI. Our anti-seizure study established a significant dose-
dependent reduction in NCS frequency and duration over a dose
range of 25–100 mg/kg (*p < .05vs. PBBI/Veh). Based on those re-
sults, Levetiracetam (50 mg/kg, 2 · the minimal effective anti-sei-
zure dose) was delivered at 30 m and 8 h post-PBBI and twice/day
thereafter for either 3 (LEV3D) or 10 (LEV10D) consecutive days.
Motor and cognitive testing were conducted using rotarod at 7 and
10 days, and Morris water maze (MWM) from 13–17 days, post-
PBBI. Results showed that the 3-day treatment regimen failed to
provide significant neuroprotection on either motor or cognitive
deficits. When the treatment was extended to 10 days, significant
improvement in functional outcome was measured. Specifically,
LEV10D-treated rats showed significant improvement in rotarod
performance (mean latency to fall at 20rpm: Sham = 43 – 5s; PBBI/
Veh = 10 – 2s; LEV3D = 18 – 5s; *LEV10D = 22 – 5s; *p < .05 LEV10D
vs. PBBI/Veh). In addition, LEV10D -treated animals displayed sig-
nificantly shorter escape latencies in the MWM test than either
LEV3D or vehicle-treated PBBI animals (Sham = 28 – 2s; PBBI/
Veh = 63 – 6s; LEV3D = 66 – 5s; *LEV10D = 48 – 5s; *p < .05 LEV10D
vs. PBBI/Veh or LEV3D). Histopathological analysis revealed no
differences across groups. Overall, Levetiracetam confers significant
therapeutic benefit in the PBBI model when an extended 10 day
dosing regimen is used. Collectively, our previous data showing
potent anti-seizure effects of this drug, combined with the current
results demonstrating significant neuroprotective effects, establish
Levetiracetam as a prime target for further study and warrants
consideration as a possible anti-seizure/neuroprotection drug can-
didate for combination therapy studies. Funded by the Army Combat
Casualty Care Research Program.
Key words
Keppra, levetiracetam, traumatic brain injury TBI
C2-11
A NOVEL SMALL MOLECULE ANTI-CYTOKINE THER-
APEUTIC ATTENUATES DOWNSTREAM COGNITIVE BE-
HAVIORAL DEFICITS IN A MOUSE MODEL OF TBI
Van Eldik, L.J.1, Webster, S.W.1, Watterson, D.M.2, Bachstetter, A.D.1
1University of Kentucky, Sanders-Brown Center on Aging, Lexington,
USA
2Northwestern University, Dept of Molecular Pharmacology & Bio-
logical Chemistry, Chicago, USA
Evidence from clinical studies and preclinical animal models
suggests that proinflammatory cytokine overproduction from acti-
vated glia is a potential driving force for pathology progression in
traumatic brain injury (TBI). This raises the possibility that se-
lective targeting of the dysregulated cytokine response, a compo-
nent of the neuroinflammation that contributes to neuronal
dysfunction, may be a useful therapeutic approach. MW01-2-
151WH (MW151) is a novel, CNS-penetrant small molecule drug
that selectively restores injury- or disease-induced overproduction
of proinflammatory cytokines towards homeostasis. We have pre-
viously reported that MW151 administered post injury is effica-
cious in a closed head injury (CHI) model of diffuse TBI in mice.
Current studies are exploring optimal dosing in this model. For
example, we are currently exploring the neurologic outcomes after
multiple drug administrations post-injury during different time
windows after injury. Initial results demonstrate that post-injury
administrations of MW151 can completely ameliorate the cognitive
deficits associated with the CHI. Our results continue to elucidate
in standard preclinical models the critical aspect of dosing that
includes repeat administration during the pharmacological mech-
anism of action time window. This knowledge is critical to the
improvement of later phase 2 clinical trial designs and add to the
criteria for Go/NoGo decisions on therapeutic development based
on mechanisms of pathology progression that are characterized by
proinflammatory cytokine overproduction. Support: KSCHIRT
Grant 12-20A (LVE)
Key words
chemokine, closed head injury, cytokine, drug discovery, microglia,
radial arm water maze
C2-12
DEFINING HOW TSG-6 IMPROVES LONG TERM MEMORY
AFTER TRAUMATIC BRAIN INJURY IN MICE
Nishida, H., Watanabe, J., Kim, D., Shetty, A.K., Prockop, D.J.
Texas A&M Health Science Center College of Medicine at Scott &
White, Institute for Regenerative Medicine, Temple, USA
Administration of mesenchymal stem/stromal cells (MSCs) was
previously observed to produce beneficial effects in models of TBI
as well as other disease models. In several models, the beneficial
effects were explained by the MSCs being activated to express TSG-
6, a naturally occurring protein that modulates inflammation. In a
mouse model of TBI produced by controlled cortical impact (CCI),
we recently found (Watanabe et al. Neurobiol Dis 2013;59:86-99)
that IV administration of recombinant TSG-6 during an initial mild
phase of neuroinflammation decreased neutrophil extravasation,
expression of matrix metalloproteinase 9 by endothelial cells and
neutrophils, and the subsequent blood brain barrier leakage in sec-
ondary phase. It also decreased the lesion size at 2 weeks. Im-
portantly, the acute administration of TSG-6 within 24 hour of TBI
was followed 6 to 10 weeks later by improvements in memory,
depressive-like behavior and the number of newly born-neurons.
Here we found that 6 hr after IV administration of TSG-6, the re-
combinant protein was found in spleen but not at significant levels in
other tissues. Also we found that plasma levels of S100b and pNF-H
correlated with severity of CCI. The results provide a basis for de-
fining in greater detail the beneficial effects in TBI of TSG-6, a
protein that has a unique mode of action and that has not been
observed to produce the adverse effects of steroids and other anti-
inflammatory agents.
Key words
MSC, spleen, TBI, TSG-6
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