Page 119 - NNS 2014 Program & Abstract Book

levels for GAPDH were not affected by TBI or EP treatments. Cy-
tosolic levels of heme oxygenase 1 (HO-1) protein and nuclear levels
of poly(ADP)-ribosylated (PAR) proteins were significantly increased
above sham levels in the TBI (p < 0.05 and p < 0.01, respectively) and
TBI-EP (p < 0.01, p < 0.001, respectively) groups, but these markers of
oxidative stress did not differ between the TBI and TBI-EP groups
(n = 4-5/group). The NAD + levels in cytosolic fractions were signif-
icantly reduced by TBI (p < 0.001 vs. sham) and, while NAD + levels
were higher in TBI-EP compared to TBI, NAD+ remained signifi-
cantly reduced in the TBI-EP group compared to sham operates
(p < 0.01; n = 11-12/group). GAPDH enzyme activity in cytosolic
fractions was significantly reduced by TBI (p < 0.01 vs. sham). EP
treatments after TBI improved GAPDH enzyme activity to a level not
significantly different from sham levels, but this improvement was
also not significant compared to TBI only controls (n = 11-12/group).
These findings are consistent with concepts that TBI-induced activa-
tion of nuclear poly(ADP-ribose) polymerase-1 (PARP-1) consumes
cytosolic NAD + to form PAR polymers, and the reduced NAD +
impacts on redox reactions including glycolysis. The ability of EP
treatments to mildly improve cytosolic levels of NAD + and GAPDH
enzyme activity by 7 h post-TBI may explain how EP improves ce-
rebral metabolic rates for glucose at 24 h after injury.
Support: NS058489 and UCLA BIRC
Key words
CCI, GAPDH enzyme, NAD, oxidative stress, pyruvate
C2-30
REMOTE ISCHEMIC PRECONDITIONING (RIPREC) PRO-
TECTS FROM TRAUMATIC BRAIN INJURY (TBI)
Vaibhav, K., Baban, B., Khan, M.B., Liu, J.Y., Huo, Y., Hess, D.C.,
Dhandapani, K.M., Hoda, M.N.
Georgia Regents University, Augusta GA, USA
TBI is a major cause of disability, which needs a safe therapy
suitable for use in fileds, pre-hospital and clinical settings. We
previously reported that remote ischemic conditioning (RIC) dur-
ing stroke improves cerebral blood flow (CBF) and functional
outcomes (Hoda et al). In this work, we hypothesized that RIPreC
will prevent post-TBI ischemia, injury and inflammation, and will
upregulate endogenous protection via AMP-activated kinase
(AMPK).
Bilateral RIPreC for 7 days before TBI (RIPreC + TBI), RIPreC
sham with TBI (TBI-group) or related sham procedures (Sham-group)
were performed as reported (Hoda MN et al 2014) in WT C57/B6 and
AMPK alpha1 knock out (AMPKa 1 - / - ) male mice (* 4-mo; n = 5/
group). TBI was performed by severe controlled cortical impact. CBF
was determined using laser speckle imager. Results were compared by
t-test and ANOVA, as needed (P < 0.05).
Acute CBF immediately after TBI was not significantly different
in the TBI-group vs. RIPreC + TBI. However, RIPreC + TBI-group
showed significant improvement in CBF at 24-hrs, and robustly
prevented the progression of tissue injury as detected by H&E and
cresyl violet staining. Gene expressions of adhesion molecules
(ICAM, VCAM, Selectins) in the brain were significantly increased
in the TBI-group as compared to Sham at 24-hrs, and was down-
regulated in the RIPreC + TBI-group. Moreover, circulating endo-
thelial progenitor cells (EPCs) and M2-type anti-inflammatory
macrophage remained unchanged in TBI-group at 24-hrs but they
were strongly upregulated in RIPreC + TBI-group. Circulating pro-
inflammatory (M1-type) macrophage was significantly increased in
the TBI-group as compared to Sham, which was downregulated in
the RIPreC + TBI-group. RIPreC failed to improve CBF and prevent
ischemic injury in AMPKa1 - / - mice. Genetic deletion of AMP-
Ka1 also abolished the benefits of RIPreC in increasing EPCs and
M2-type macrophage.
RIPreC is promising for the prevention of post-TBI injury and can
be easily translated into subjects at high risk (soldiers and athletes).
Since RIPreC increases circulating EPCs and M2-type macrophage,
further studies are warranted for various RIC paradigms (Pre- and
Post) in neurovascular protection and neurorestoration after TBI.
Key words
AMP-activated kinase, cerebral blood flow, remote ischemic condi-
tioning, TBI
C2-31
MEMANTINE HYDROCHLORIDE AS A THERAPY FOR
TRAUMATIC BRAIN INJURY: A PRECLINICAL STUDY
USING THE CCI INJURY MODEL IN RATS
Abrahamson, E.E.1,2, Foley, L.M.5, Hitchens, T.K.5, Dixon, C.E.4,
Ikonomovic, M.D.1–3
1Geriatric Research Education and Clinical Center, VA Pittsburgh
Healthcare System, Pittsburgh, PA, USA
2University of Pittsburgh, Department of Neurology, Pittsburgh, PA,
USA
3University of Pittsburgh, Department of Psychiatry, Pittsburgh, PA,
USA
4University of Pittsburgh, Department of Neurosurgery, Pittsburgh,
PA, USA
5Carnegie Mellon University, Pittsburgh NMR Center, Pittsburgh,
PA, USA
Traumatic brain injury (TBI) results in glutamate release above
physiological levels, which contributes to neuronal dysfunction.
Memantine hydrochloride is a clinically well-tolerated moderate-
affinity noncompetitive glutamate receptor antagonist with potential
utility in TBI. We assessed the effects of memantine administration
after controlled cortical impact (CCI) injury in adult rats, using a
clinically-relevant dosing paradigm. Memantine (2.5, 5, 10 mg/kg) or
vehicle was administered daily for 3 weeks starting 1 hr after CCI
injury, by intraperitoneal injection during the first 4 days and there-
after per os over an additional 17 days. Measured histological vari-
ables included cortical tissue preservation, and cell number and
synapse density in the hippocampus. Cerebral blood flow (CBF) was
evaluated by arterial spin-label MR imaging. Behavioral testing in-
cluded beam balance, beam walking, and Morris water maze tests.
Hippocampal synapse density was preserved in rats treated with
10 mg/kg memantine. No differences were detected in cortical tissue
preservation in memantine-treated groups compared to the vehicle-
treated group. CBF deficits in the injured hemisphere were ameliorated
by treatment with 10mg/kg memantine. Rats treated with 10mg/kg
memantine recovered faster on the beam balance test, however no ef-
fects of treatment were observed in the beam walking test or the Morris
water maze test. Collectively, these results demonstrate that in the adult
rat CCI model, daily treatment with memantine over three weeks re-
duces cell and synapse loss and ameliorates CBF deficits. These data
are consistent with reports of beneficial effects of memantine treatment
in other brain injury paradigms including rat stroke models, and in
patients with vascular dementia.
Key words
cerebral blood flow, controlled cortical impact, excitotoxicity,
glutamate
A-87