Page 113 - NNS 2014 Program & Abstract Book

C2-13
A COMPARATIVE EVALUATION OF MEMANTINE AND
TOPIRAMATE: NO EVIDENCE OF FUNCTIONAL RE-
COVERY FOLLOWING TRAUMATIC BRAIN INJURY
Elmore, B.E.1, Anderson, G.D.2, Wright, A.M.1, Kantor, E.D.2, Hoane,
M.R.1
1Southern Illinois University Carbondale, Department of Psychology,
Carbondale, IL, United States
2University of Washington, Department of Pharmacy, Seattle, WA,
United States
The purpose of this study was to investigate and compare the thera-
peutic potential of two drugs, memantine and topiramate, on functional
recovery utilizing clinically relevant doses. Memantine is a NMDA
antagonist currently approved for use in Alzheimer’s disease. Topir-
amate augments the function of GABA and is commonly used as an
anticonvulsant. A multimodal behavioral assessment was conducted
following induction of TBI. Subjects were randomly assigned to one of
five groups: TBI + low dose memantine (5mg/kg), TBI + high dose
memantine (20mg/kg), TBI + topiramate (10mg/kg), TBI + vehicle
(0.9% saline), and Sham + vehicle. Injuries were induced using a pari-
etal controlled cortical impact (CCI) model. Treatments were admin-
istered via i.p. injections starting at 4 hours post-injury, followed by
administrations every 12 hours for 48 hours. Motor and cognitive
function was assessed using a variety of tasks used routinely in the lab.
Gene expression was determined using microarray and gene ontology
analysis in additional groups of animals at 24 h, 72 h and 7 days post-
CCI. Neither memantine nor topiramate improved motor or cognitive
function. Gene expression studies found that both drugs significantly
affected dopaminergic synaptic transmission at 24 h and inflammatory
response at 72 h after injury. These results indicate that while mem-
antine and topiramate may provide benefits for other neurological
conditions, their therapeutic potential following TBI appears limited.
Key words
behavior, CCI, memantine, pharmaceutical, recovery of function,
topiramate
C2-14
EVALUATION OF SIMVASTATIN IN THE WRAIR PBBI
MODEL: STUDIES FROM THE OPERATION BRAIN TRAU-
MA THERAPY (OBTT) CONSORTIUM
Mountney, A., Readnower, R., Cunningham, T., Pedersen, R., Sun, J.,
Flerlage, J., Caudle, K., Schmid, K., Tortella, F.C., Shear, D.A.
Walter Reed Army Institute of Research, Silver Spring, USA
Operation Brain Trauma Therapy (OBTT) is a multi-center consor-
tium established to provide cross-model preclinical screening of
emerging TBI therapies. Simvastatin, a 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor, is used clinically to reduce serum
cholesterol. Additionally, Simvastatin has demonstrated potent anti-
neuroinflammatory and brain edema reducing effects, showing promise
in preclinical models of traumatic brain injury (TBI). This study assesed
the potential therapeutic effect of oral Simvastatin on neurobehavioral
recovery in the WRAIR penetrating ballistic-like brain injury (PBBI)
model. Unilateral frontal PBBI was produced in the right hemisphere of
anesthetized rats. Simvastatin was dosed via oral gavage at 0 (vehicle),
1.0 and 5.0mg/kg starting at 3 h post-injury and once/day thereafter for
14 days. Motor function was evaluated on the Rotarod and cognitive
performance was evaluated on the Morris water maze (MWM). Brains
were processed for histopathological analysis. Rotarod testing revealed
motor deficits in all injury groups with overall mean latencies reduced
by 39 – 10% (vehicle), 32 – 11% (1.0 mg/kg), and 30 – 1% (5.0 mg/kg)
with significant performance decrements detected in PBBI + vehicle
animals only (p < .05 vs sham). In contrast, an intermediate treatment
effect of Simvastatin (both doses) towards improved motor performace
was evident at 10 days post-injury. Cognitive performance in the
MWM revealed deficits in all injury groups with the average latency to
find the hidden platform (across all testing days) increased by 70 – 13%
(vehicle), 68 – 16% (1.0 mg/kg), and 87 – 13% (5.0 mg/kg) vs. sham
(p < .05). No significant therapeutic effects were detected on MWM
parameters or on histological metrics. Overall, the results of this study
indicate that sustained, oral administration of Simvastatin produces
modest motor benefit but is ineffective in promoting significant neu-
rofunctional and/or histopathological recovery in the PBBI rat model.
Supported by U.S. Army Grant W81XWH-10-1-0623
Key words
neuroprotection, OBTT, PBBI, simvastatin, TBI
C2-15
EARLY GLUCOSE SUPPLEMENTATION FOLLOWING
CONTROLLED CORTICAL IMPACT INJURY DOES NOT
ALTER OXIDATIVE METABOLISM 24 HRS POST-INJURY
Bartnik-Olson, B.L.1, Shijo, K.2, Ghavim, S.3 , Harris, N.G.3, Sutton,
R.L.3
1Loma Linda University, Loma Linda, USA
2Nihon University School of Medicine, Tokyo, Japan
3University of California Los Angeles, Los Angeles, USA
Following TBI, extracellular glucose levels are frequently reduced and
predictive of poor outcome suggesting that endogenous fuels may not be
sufficient to meet metabolic demands. We reported that exogenous glu-
cose treatments over 6 hrs after controlled cortical impact (CCI) injury
resulted in improved cerebral metabolism and neuronal survival at 24 hrs
after injury. The purpose of this study is to determine if glucose sup-
plementation immediately after injury influences the activity of metabolic
pathways associated with oxidative metabolism and the intracellular re-
dox state. Sixteen male rats underwent a moderate-severe CCI with an
additional 8 rats receiving anesthesia only (Control). CCI-injured animals
received an i.p. injection of glucose (CCI-Glc; 2000mg/kg, n =8) or 8%
saline (CCI-SAL; n = 8) at 0, 1, 3, 6 and 23 hrs post-injury. At 24 hrs
post-injury animals were infused with [1, 2 13C2] glucose for 60 minutes.
Following infusion, animals were euthanized and extracts of the injury
cortex and hippocampus were prepared. Proton decoupled 13C NMR
spectra were obtained on a Bruker Avance 500MHz spectrometer. The
amount of 13C in each metabolite isotopomer was quantified using so-
dium 3-(trimethylsilyl) propionate. Between group differences were
measured using a one-way ANOVA with a post-hoc Bonferrroni com-
parison. Compared to controls, the total amount of 13C labeled glutamate
(p < 0.001) and glutamine (p = 0.05) was significantly lower in the injured
hemisphere of CCI-injured groups. Glucose metabolism via the pentose
phosphate pathway (PPP) trended lower in the CCI-Glc group, but did
not reach significance (p = 0.18 vs. control). These results indicate that
glucose supplementation beginning immediately post-CCI did not im-
prove neuronal and astrocyte oxidative metabolism (i.e. 13C enrichment
of glutamate and glutamine), nor did glucose treatments significantly
impact cellular redox state (i.e. PPP) at 24 hrs post-injury.
Key words
13C spectroscopy, glucose, intracellular redox state, oxidative me-
tabolism
A-81