Page 136 - NNS 2014 Program & Abstract Book

composite motor/cognitive score for isobolic analysis using the con-
cept of dose equivalence. Results revealed a moderate trend towards
improved motor performance with an intermediate treatment effect
detected at the highest dose-ratio tested. In contrast, significant dose-
dependent improvements were detected on the MWM task evident on
measures of latency to locate the hidden platform and in percent time
spent swimming around the outer perimeter of the water maze. Iso-
bolic analysis of the composite motor/cognitive score showed clear
additivity for the combination confirming that the dose of one drug
can be reduced when combined with the other and in quantities that
are consistent with their individual potencies.
Key words
cognitive, combination therapy, motor, PBBI, TBI
D1-10
THROMBIN DECREASES EXPRESSION OF GLAST AND
INHIBITS GLUTAMATE UPTAKE IN ASTROCYTES VIA
THE RHO KINASE PATHWAY
Rusie, A.1, Ralay Ranaivo, H.1,2, Wainwright, M.S.1,2
1Ann & Robert H. Lurie Children
Preclinical and clinical studies suggest that breach of the blood brain
barrier (BBB) leading to extravasation of the serum proteins such as
thrombin contribute to the mechanisms of post-traumatic epilepsy
(PTE). The astrocyte glutamate transporters GLAST and GLT1 play a
key role in regulating neuronal excitation and their levels are de-
creased after TBI. We examined the effects of thrombin on the ex-
pression and function of glutamate transporters in isolated rat cortical
astrocytes.
Primary astrocytes were exposed to thrombin or PAR-1 activating
peptide. After 24 hr recovery, GLAST and GLT1 levels were quan-
tified by Western blotting. Glutamate uptake was measured using an
enzymatic assay.
Thrombin induced a decrease in the expression of GLAST, with a
corresponding decrease in the capacity of astrocytes to take up glu-
tamate. Activation of the thrombin receptor PAR-1 with an activating
peptide induced a similar decrease in the expression of GLAST and
compromise of glutamate uptake. The downregulation of GLAST
induced by thrombin was mediated by the mitogen activated protein
kinases p38 MAPK, ERK and JNK, but inhibition of these kinases did
not prevent the decrease in glutamate uptake induced by thrombin. In
contrast, inhibition of the Rho kinase pathway using the specific in-
hibitor, Y27632, suppressed both the decrease in the expression of
GLAST and the decrease in glutamate uptake induced by thrombin.
These results identify a novel mechanism for the regulation of
glutamate transporters following disruption of the BBB, and implicate
thrombin in the mechanisms of PTE.
Key words
glutamate, MAPK, proteases, RhoK
D1-11
REMOTE-ISCHEMIC PRECONDITIONING AS A PROPHY-
LACTIC METHOD TO INCREASE BIOLOGICAL RESI-
LIENCE TO MILD TRAUMATIC BRAIN INJURY
Park, E.1 , Lallani, M.N.1, Baker, A.J.1–3
1St. Michael’s Hospital, Li Ka Shing Knowledge Institute, Toronto,
Canada
2University of Toronto, Departments of Anesthesia and Surgery,
Toronto, Canada
3St. Michael’s Hospital, Department of Critical Care, Toronto, Ca-
nada
Mild traumatic brain injury (mTBI) accounts for the largest proportion
of brain injury cases. Sports injuries and military trauma in particular
have high incidences of repetitive mTBI occurrences. While the
majority of cases resolve over time, a significant proportion of mTBI
cases report ingoing neurological issues. Treatment to reduce the
secondary cellular injury mechanisms in these vulnerable groups re-
mains elusive. We previously developed a model of mTBI using a
shock wave generating device which demonstrates hallmark features
of white matter pathophysiology and persistent neurobehavioural
deficits relevant to mTBI. Remote-ischemic preconditioning (rIPC)
has been shown to provide protection to tissues sensitive to ischemic
stress. Given the overlap in final common pathways found in ischemic
injury as well as cellular mechanisms of secondary injury progression
in mTBI, we hypothesized that rIPC would provide therapeutic benefit
in a model of mTBI. rIPC was evaluated as a potential prophylactic
treatment for mTBI incurred through primary blast exposure. An-
esthetized adult male Sprague-Dawley rats were subject to 4 cycles of
hind-limb ischemia applied for 5 minutes followed by 5 minutes of
reperfusion. A control group consisted of rats subjected only to an-
esthesia. Twenty-four hours after rIPC treatment, rats were exposed to
a * 40 kPa primary blast. Preliminary results indicate a reduction in
aII-spectrin breakdown in the corpus callosum with rIPC treatment,
independent of protective effects exerted by isoflurane precondition-
ing. rIPC also modulated the heavy neurofilament response to primary
blast trauma. Immunoblotting for HIF-1a indicated a lack of expres-
sion in all injury groups suggesting that ischemia did not play a role in
the blast mTBI model. The current results suggest that rIPC may
reduce pathophysiological response after mTBI, independent of is-
chemic signalling pathways. Furthermore, the rIPC treatment may
represent a simple and non-invasive means of augmenting endogenous
biological resilience to mTBI.
Key words
mild TBI, primary blast, remote ischemic preconditioning, resilience,
subclinical
D1-12
ACUTE INTERLEUKIN-6 TRAJECTORIES AFTER TBI: RE-
LATIONSHIP TO ISOLATED INJURY AND POLYTRAUMA
AND ASSOCIATIONS WITH OUTCOME
Kumar, R.G.1, Diamond, M.L.1, Boles, J.A.1, Carlisle, K.M.1, Berger,
R.P.3,4, Tisherman, S.4–6, Kochanek, P.M.4,6, Wagner, A.K.1–3
1Department of PM&R, Pittsburgh, USA
2Center for Neuroscience, Pittsburgh, USA
3Department of Pediatrics, Pittsburgh, USA
4Safar Center for Resuscitation Research, Pittsburgh, USA
5Department of Surgery, Pittsburgh, USA
6Department of Critical Care, University of Pittsburgh, Pittsburgh,
USA
Due to the heterogeneity of injury patterns in traumatic brain injury
(TBI), characterization of pathophysiology observed in isolated TBI
compared with TBI + polytrauma is needed. Interleukin-6 (IL-6) is a
pro-inflammatory cytokine known to be elevated after major trauma.
We examined whether IL-6 temporal profiles (trajectories) differ in
isolated TBI versus TBI + polytrauma and whether these profiles
predict outcome. Injury type was dichotomized as ‘isolated’ or
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