Page 110 - NNS 2014 Program & Abstract Book

among the four dose ratios tested, the highest dose ratio (14.4/44.4
mg/kg) significantly reduced the overall incidence of NCS from
69% (vehicle group) to 29% (PHT + EXM group), decreased NCS
frequency by 80% (Vehicle: 14.3 – 5.5 NCS episodes/rat vs.
PHT + EXM: 2.8 – 1.3 episodes/rat), and shortened NCS cumulative
duration by 84% (Vehicle: 502.8 – 277 sec/rat vs. PHT/EXM:
82.5 – 38.1 sec/rat). The PHT + EXM combination treatment also
significantly delayed onset latency of NCS from 20 – 4.4 h post
PBBI (vehicle) to 53 – 7.9 h (PHT + EXM). More importantly,
compared to the effective monotherapy doses of PHT and EXM as
mentioned above, the PHT + EXM combination therapy proved to
be equally efficacious without overt sedation using 28% less PHT
and 64% less EXM, which resulted in an additive effect as defined
by the isobolographic analysis. This study supports the idea that
combination therapy enhances the effectiveness of the drug con-
stituents and provides improved therapeutic benefits by limiting
potential side effects of individual drugs.
Key words
anti-seizure combination therapy, ethosuximide, penetrating brain
injury, phenytoin
C2-05
THERAPEUTIC WINDOW FOR SELECTIVE BRAIN COOL-
ING FOLLOWING PENETRATING BALLISTIC-LIKE BRAIN
INJURY IN RATS
Wei, G., Yang, X.Y., Shear, D.A., Tortella, F.C.
Walter Reed Army Institute of Research, Silver Spring, USA
Previous work has shown that 4 h selective brain cooling (SBC)
initiated immediately following penetrating ballistic-like brain in-
jury (PBBI) improves the injury-induced motor function in rats. The
current study was designed to determine the delayed therapeutic
window of SBC on motor function following PBBI. Unilateral
frontal PBBI was produced in the right hemisphere of isoflurane
anesthetized rats (10% injury severity level). SBC (34 C for 4 h) was
induced via extraluminal cooling of the bilateral common carotid
arteries, initiated at 2 h or 4 h after PBBI and continuously main-
tained under anaesthesia for 4 h. Sham and control rats (PBBI alone)
were exposed to identical procedures as SBC (including being
maintained under anaesthesia for up to 4 h) without the cooling of
the brain. Neuroprotective efficacy was measured on the fixed-speed
rotarod task to measure motor coordination and balance from 7 to 14
days post-injury (DPI). When SBC was delayed to 2 h post-PBBI
(SBC2 h), significant improvement in motor function was detected at
7 DPI (mean rotarod latencies: Sham = 55 – 3s; PBBI = 15 – 3s;
*PBBI + SBC2 h = 28 – 3s; *p < .05 SBC 2 h vs. PBBI) that was sus-
tained out to 14 DPI (Sham = 58 – 2s; PBBI = 19 – 5s; *PBBI +
SBC2 h = 36 – 3s; *p < .05 SBC2 h vs. PBBI). When SBC was delayed
to 4 h post-PBBI (SBC4 h), a trend towards improved performance
was evident, but no significant improvement in motor performance
was detected at either 7 DPI (Sham = 53 – 1s; PBBI = 20 – 1;
PBBI + SBC4 h = 23 – 2s) or 14 DPI (Sham = 60 – 0s; PBBI = 18 – 5;
PBBI + SBC4 h = 22 – 4s). No adverse effects were detected from
SBC-treated rats regardless of when treatment was initiated. Collec-
tively, these results suggest that SBC treatment provides therapeutic
benefit in the absence of adverse effects, even when delayed up to 4 h
post-injury. However, in order to achieve optimal therapeutic benefit
SBC treatment should be initiated within 2 h post-injury.
Key words
function, hypothermia, penetrating brain injury, therapeutic window
C2-06
SELECTIVE ASTROCYTE OVEREXPRESSION OF HEME
OXYGENASE-1 IS PROTECTIVE AFTER INTRACEREBRAL
HEMORRHAGE
Chen-Roetling, J.1, Song, W.2, Schipper, H.M.2, Regan, R.F.1
1Thomas Jefferson University, Philadelphia, USA
2Lady Davis Institute, Jewish General Hospital, Montreal, Canada
Heme oxygenase-1 (HO-1) catalyzes the rate-limiting reaction of
heme breakdown, and may have both antioxidant and pro-oxidant
effects. In prior studies, HO-1 overexpression protected astrocytes
from acute heme-mediated injury in vitro; conversely, unconditional
HO-1 knockout was beneficial in vivo after ICH. In the present study,
we tested the hypothesis that selective astrocyte overexpression of
HO-1 improves outcome after intracerebral hemorrhage (ICH).
Male and female transgenic mice overexpressing human HO-1
driven by the GFAP promoter (GFAP.HMOX1) and wild-type FVB
controls were injected with 25 ll autologous blood into the right
striatum under stereotactic guidance. Blood-brain barrier disruption
was assessed by Evans blue assay, and perihematomal cell viability by
MTT assay. Neurological deficits were quantified by adhesive re-
moval, corner, and elevated body swing tests, and by digital analysis
of spontaneous cage activity. Mortality data were analyzed with
Fisher’s exact test; other data were analyzed with one-way ANOVA
and the Bonferroni multiple comparisons test.
Striatal blood injection resulted in death of 25% of WT mice within
24 hours; all GFAP.HMOX1 mice survived (P = 0.0048). Striatal Evans
blue leakage at 24 hours was 23.4 + / - 3.2 ng in surviving WT mice,
compared with 10.9 + / - 1.8 ng in transgenics (P < 0.001). Perihemato-
mal cell viability was reduced to 61 – 4% of contralateral at 3 days in
WT mice, v. 80 – 4% in transgenics (P < 0.05). Focal neurological
deficits were significantly reduced in GFAP.HMOX1 mice (P < 0.001),
and spontaneous cage activity was increased (P < 0.05).
Selective HO-1 overexpression in astrocytes reduces blood-brain
barrier disruption, perihematomal cell injury, neurological deficits,
and mortality in an autologous blood injection ICH model. Genetic or
pharmacologic therapies that transiently increase astrocyte HO-1 ex-
pression may be beneficial after ICH. The present findings contrast
with the deleterious effects of acute HO-1 induction in other cell
populations after ICH and chronic overexpression in neurodegenera-
tive disease models, which are likely mediated by iron release.
Acknowledgment
Supported by NIH/NINDS R01NS079500.
Key words
heme, hemorrhage, iron, stroke
C2-07
DOSE-RESPONSE EVALUATION OF LEVETIRACETAM IN
THE MIAMI FLUID PERCUSSION MODEL OF TRAUMATIC
BRAIN INJURY: AN OBTT CONSORTIUM STUDY
Bramlett, H.M. , Furones-Alonso, O., Sanchez-Molano, J., Sequiera,
D., Moreno, W., Dietrich, W.D.
University of Miami Miller School of Medicine, Department of
Neurlogical Surgery, Miami, USA
Levetiracetam is currently used after clinical traumatic brain injury
(TBI) to target seizures. A few studies have suggested beneficial ef-
fects of levetiracetam following experimental TBI. Thus, it was
chosen as the fifth drug to be tested by the multicenter consortium
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