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Introduction:
The neurological consequences of traumatic brain in-
jury worsen when the injury is complicated by hypotension. A new
class of 2
·
40 nm carbon nanoparticle antioxidants, poly(ethylene
glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs) had
been previously shown to rapidly restore cerebral blood flow (CBF)
and neutralize reactive oxygen species in a mild cortical impact injury
complicated by hypotension (mCCI
+
HT) model, when administered
during resuscitation. The purpose of this research was to study long
term neurological outcome following administration of PEG-HCCs in
mCCI
+
HT model.
Methods:
Thirty two Long Evans rats, weighing 300–350 grams,
were randomly assigned to two groups: saline-treated (n
=
16) and
PEG-HCC treated (n
=
16). All rats were anesthetized with isoflurane
and subjected to a mCCI [3 m/sec, 2.5 mm deformation], followed by
a hypotensive phase for 50 minutes (mean arterial pressure or
MAP
< =
40), a prehospital phase for 30 minutes (infusion of Lactate
Ringer’s until MAP
> =
50), and a hospital phase of 30 minutes where
the shed blood was reinfused while breathing 100% oxygen. Saline or
PEG-HCC (2 mg/kg) were administered IV at the beginning of re-
suscitation and again two hours after the first injection. Behavioral
outcome measures included beam walking and balance tests on days
1–5, and Morris water maze on days 11–15. The rodents were eu-
thanized and histological measures were performed.
Results:
Performance during beam walking and balancing were
significantly improved in the PEG-HCC treated group when compared
to saline-treated groups (P
=
0.007, P
>
0.001 respectively). Treatment
with PEG-HCC also improved the latency of finding the platform was
significantly faster on the first day of Morris water maze when com-
pared to the saline-treated group (Treatment X Day, P
<
0.001). There
was a trend in the differences in contusion volumes (P
=
0.054).
Conclusions:
PEG-HCCs have been shown to restore CBF as well
as neutralize dangerous reactive oxygen species. This study demon-
strates that PEG-HCCs also improve neurological recovery.
Keywords: Nanoparticles, antioxidants, brain injury, PEG-HCC,
hypotension, reactive oxygen species
D8-03
NEUROPROTECTIVE EFFICACY OF ERYTHROPOIETIN-
MIMETIC PEPTIDE (ARA290) WITH DELAYED ADMINIS-
TRATION AFTER CORTICAL IMPACT INJURY
Leela Mathew
1
, Roberto Garcia
1
, Carlos Estevez-Castillo
1
, Ammar
Husan
1
, Lamin Mbye
1
, Charles Milard
1
, Jerry Goodman
1
, Carla
Cerami
2
, Claudia Robertson
1
1
Baylor College of Medicine, Neurosurgery, Houston, USA
2
University of North Carolina, Public Health, North Carolina, USA
Objectives:
ARA290, an erythropoietin-mimetic peptide that does not
stimulate erythropoiesis, improved neurological outcome at two
weeks following severe cortical impact injury (sCCI) when given in a
dose of 30 mg/kg q12h for 3 days starting one hour post-injury. The
objective of this study was to determine neuroprotective efficacy of
ARA 290, delaying the first dose until 3 hours after injury and with
more long-term (30 day) outcome.
Methods:
192 male rats underwent sCCI and were randomly as-
signed to different IV treatment regimens (continuous infusion, q6h,
q12h, or q24h) for 3 days starting at 3 hours post-injury. Primary
outcome measure was a composite neurological score of behavioral
performance (beam walking and Morris water maze) and histological
measures (CA1 cell count). Individual tests were analyzed as sec-
ondary outcomes. For q6h and q24h dosing groups, the experiment
was subsequently repeated with a more difficult Morris water maze
task at four weeks post-injury (reversing platform position with
smaller platform).
Results:
Composite neurological outcome score was significantly
better in the ARA290 treated animals than in the vehicle treated an-
imals (score difference 0.22
–
0.10, P
=
0.037). Best composite score
occurred with q24h (score difference 0.54
–
0.21, P
=
0.013). The ef-
fect of drug treatment did not depend on the dosing regimen. The
motor tasks were significantly better in the ARA290 group (beam
walking test, p
=
0.0003 and beam balance test, p
=
0.05). Performance
on the Morris water maze task was not improved in the ARA290
treated animals with the standard testing procedure. However, when
the study was repeated with the more difficult Morris water maze task,
ARA290 treated animals in the q24h dosing regimen group had sig-
nificantly improved performance.
Conclusions:
ARA290 significantly improved long-term neuro-
logical recovery when treatment was started at 3 hours post-injury,
and continuous infusion of ARA290 did not provide better neuro-
protection than the intermittent dosing regimens.
Keywords: Cortical Impact Injury, ERYTHROPOIETIN - MI-
METIC PEPTIDE (ARA290)
D8-04
LITHIUM AND VALPROATE ADMINISTRATION PROVIDES
NEUROPROTECTION AFTER MILD TRAUMATIC BRAIN
INJURY COMPLICATED BY HYPOTENSION
Ammar Husan
1
, Roberto Garcia
1
, Lamin Mbye
1
, Pramod Dash
2
,
Claudia Robertson
1
1
Baylor college of Medicine, Neurosurgery, Houston, USA
2
University of Texas Health Science Center, Neurobiology And
Anatomy, Houston, USA
Introduction:
Lithium (Li) and Valproate (VPA) are two antiepileptic
drugs that are shown to be neuroprotective, due in part to inhibition of
glycogen synthase kinase-3 (GSK-3) and histone deacetylases
(HDACs), respectively. The purpose of this research was to study
neurological outcomes, following administration of Li-VAP in mild
controlled cortical impact (mCCI) injury, complicated by hypotention
(HT) in the rodent model.
Methods:
A total of 32 Long Evans rats, weighing 300–350 grams,
were randomly assigned to two groups: saline-treated (n
=
16) and
Li
+
VAP treated (n
=
16). All rats were anesthetized with isoflurane
and subjected to a mCCI ([3 m/sec, 2.5 mm deformation]), followed
by a hypotensive phase for 50 minutes (mean arterial pressure or
MAP
< =
40), a prehospital phase for 30 minutes (infusion of Lactate
Ringer’s until MAP
> =
50), and a hospital phase of 30 minutes where
the shed blood was reinfused while breathing 100% oxygen. Both
groups were given q24h x 4 intraperitoneal (IP) injections of either
saline or Li (20 mg/kg)
+
VPA (42 mg/kg), with the first dose admin-
istered at the beginning of resuscitation. Behavioral outcome mea-
sures included beam walking and beam balancing tests for motor
coordination at days 1–5, and Morris water maze (MWM) for spatial
navigation days 11–15. After 15 days, animals were euthanized and
histological measures were performed.
Results:
Performance during beam walking and balancing were
significantly improved in the Li-VAP treated group when compared to
saline-treated groups (P
=
0.006, P
=
.003 respectively). Li-VAP ad-
ministration also significantly improved latency of hidden platform
location on the first day of MWM when compared to the saline-treated
group (Treatment X Day, P
<
0.001).
Conclusions:
Compromised cerebral blood flow following brain
injury due to HT further complicates the outcome and rehabilitation in
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