Page 114 - NNS 2014 Program & Abstract Book

C2-16
NEUROPROTECTIVE EFFECTS OF NOVEL THERAPEUTIC
NNZ-2591 FOLLOWING PENETRATING TBI
Cartagena, C.M., Swiercz, A., Johnson, D., Deng-Bryant, Y., Boutte,
A.M., Tortella, F.C., Schmid, K.E.
WRAIR, Silver Spring, MD, USA
NNZ-2591 is a synthetic analog of the neuropeptide cyclic glycine-
proline (cGP), an active metabolite of the neuropeptide glycine-
proline-glutamate (GPE) or (1-3)IGF-1 which is cleaved from the
n-terminus of IGF-1. NNZ-2566, a synthetic analog of (1-3)IGF-1, is
currently in clinical trials for TBI, Fragile X syndrome, and Rett
syndrome. NNZ-2566 reduces post-injury inflammatory mechanisms
and preserves cognitive and motor system function following pene-
trating ballistic-like brain injury (PBBI). While NNZ-2566 is ap-
proximately 45–50% orally bioavailable, NNZ-2591 exhibits 100%
oral bioavailability. Here, we investigate whether, like NNZ-2566,
NNZ-2591 has anti-inflammatory activity, and if it regulates genes
that govern synaptic plasticity following PBBI. Groups tested:
Sham + vehicle, PBBI + vehicle, PBBI + NNZ-2591 (30 mg/kg by oral
gavage 30 min post-injury and again once daily until endpoint). Ip-
silateral brain tissue containing the injury tract was collected 24 h,
72 h and 7 days post-injury (n = 10). IL-1beta and IL6 levels were
evaluated by ELISA. IL1beta cytokine levels were increased by PBBI:
24 h (72%, p < 0.001); 72 h (48%, p < 0.01); 7 days (17%, p < 0.05).
NNZ-2591 did not decrease IL-1beta levels at 24 h or 72 h but de-
creased levels at 7 days (7%, p < 0.05). IL6 levels were increased by
PBBI at 24 h (400%, p < 0.001) but not 72 h or 7 days. NNZ-2591
decreased IL6 levels at 24 h (33%, p < 0.05). In addition, at 7 days
NNZ-2591 reduced IL6 levels below both PBBI and sham levels 17%
(p < 0.05) and 22% (p < 0.01), respectively. In separate animals, mi-
croarrays of 83 genes involved in synaptic plasticity were evaluated at
24 h post-injury (n = 4). Gene array analysis indicated that many genes
were altered by PBBI. NNZ-2591 mitigated PBBI induced changes
for select genes. For example, at 24 h post PBBI, NNZ-2591 increased
mRNA levels of ppp3ca (1.4 fold, p < 0.05) but decreased tnf (-1.713
fold, p < 0.05) compared to PBBI + vehicle. Continued analysis will
likely identify additional inflammatory or neuroplasticity genes al-
tered by NNZ-2591. Collectively, these results indicate that NNZ-
2591 has neuroprotective and anti-inflammatory effects following
severe TBI. Its excellent bioavailability makes it a potentially prom-
ising treatment for mild, moderate, or severe TBI.
Key words
neuroprotection, NNZ-2591, PBBI, severe TBI
C2-17
THE DEVELOPMENT OF NON-CONVULSIVE SEIZURES
FOLLOWING MILD TRAUMATIC BRAIN INJURY WITH
MILD HYPERTHERMIA IN THE RAT
McGuire, L.S.1, Wasserman, J.1, Sick, T.2, Bramlett, H.M.1, Dietrich,
W.D.1
1University of Miami Miller School of Medicine, Department of
Neurological Surgery, The Miami Project to Cure Paralysis, Miami,
FL
2University of Miami Miller School of Medicine, Department of
Neurology, Miami, FL
Post-traumatic non-convulsive seizures represent an important
clinical entity. Recent literature suggests that the majority of sei-
zures following traumatic brain injury (TBI) are non-convulsive.
Presently, few experimental studies have investigated the patho-
physiology of post-traumatic non-convulsive seizures after mild
TBI. Our laboratories have recently reported that mild elevations in
brain temperature that may occur during periods of strenuous ex-
ercise or other activities can worsen outcome after mild TBI. This
study therefore characterized the impact of mild elevations of
temperature on the development of post-traumatic seizure events.
The Marmarou weight drop model of closed-head traumatic brain
injury was used at a mild level of severity. Three groups of ani-
mals were tested: sham (n = 5), TBI-normothermia (n = 4), TBI-
hyperthermia (n = 4). Normothermia was maintained at 37 C and
hyperthermia animals at 39 C. Animals were monitored for tem-
perature for two hours following trauma. One hour video electro-
encephalography was performed at 12-weeks post-injury, and
power spectral analysis was performed in MATLAB using custom-
written software EEGgui. Behavioral testing was performed at
baseline, 1-week post-injury, and 12-weeks post-injury. Animals
were transcardially perfused at 12 weeks for histopathological
analysis. Preliminary electrophysiology data suggests an increase
in seizure susceptibility among animals with hyperthermia. Epi-
leptic events were characterized by periodic increases in ECoG
power across multiple frequency bands. Behavioral testing in these
mildly traumatized animals demonstrates few statistically signifi-
cant differences among latencies in the watermaze hidden platform,
probe, and working memory tasks. The impact of hyperthermia on
the extent of post-traumatic mild diffuse brain injury appears to be
subtle. However, mild hyperthermia appears to make neurons more
susceptible to seizure events, particularly non-convulsive seizures.
Studies are currently in progress to next determine the conse-
quences of repetitive episodes of mild TBI on the electrophysio-
logical and behavioral outcomes using these innovative monitoring
approaches. Supported by W81XWH-12-1-0618.
Key words
non-convulsive seizure, traumatic brain injury
C2-18
DIFFERENTIAL EFFECTS OF CX3CR1 OR CCR2 DELETION
IN HIPPOCAMPAL INFLAMMATORY RESPONSE FOL-
LOWING TRAUMATIC BRAIN INJURY
Morganti, J.M., Riparip, L.K., Rosi, S.
University of California, San Francisco, USA
CNS infiltrating monocytes/macrophages can be reliably divided
into two distinct subpopulations based upon their cells surface ex-
pression of two chemokine receptors, CX3CR1 or CCR2. Recent
work has shown that TBI creates a permissive environment for the
infiltration of systemic or circulating immune cells into the brain
following injury. However, in the context of TBI-initiated neuroin-
flammatory response, the relative contribution of CCR2 + or
CX3CR1 + monocytes/macrophages remains elusive. Importantly,
genetic deletion of CCR2 or CX3CR1 depletes circulating levels of
their respective monocyte subpopulations, which has shown differ-
ential effects in various neurodegenerative disease models. Herein,
we examined the effect of CCR2, CX3CR1, or combined genetic
deletions on the neuroinflammatory response in the hippocampus
following TBI. Using the controlled cortical impact model, 3 month old
CX3CR1GFP/GFP, CCR2RFP/RFP, and CX3CR1GFP/GFPCCR2RFP/RFP
mice were injured in the parietal lobe and sacrificed 24 hours fol-
lowing injury. Ipsilateral hippocampi were dissected and processed
for RNA extraction to quantify the gene expression of multiple
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