Page 140 - NNS 2014 Program & Abstract Book

mice as well as limiting white matter injury. The CHI model was then

used to titrate MINO and NAC levels. This led to an optimized MINO

(10 mg/kg) plus NAC (75 mg/kg) combination that was significantly

more potent in limiting behavioral deficits than the original MINO (45

mg/kg) plus NAC (150 mg/kg) formulation. MINO plus NAC is now

known to limit brain injury in two TBI models, and two species.

Key words

cognition, drug combinations, heterogeneity, memory, synergy

D1-21

THERAPEUTIC POTENTIAL OF THE PROSTAGLANDIN E2

EP1 RECEPTOR IN TRAUMATIC BRAIN INJURY

Glushakov, A.V.

1

, Fazal, J.A.

1

, Narumiya, S.

2

, Dore, S.

1

University of Florida, Gainesville, FL, USA

2

Kyoto University, Kyoto, Japan

Brain injuries promote upregulation largely proinflammatory prosta-

glandin E

2

(PGE

2

) leading to overactivation of a class of cognate G-

protein coupled receptors, notably EP1 receptor involved in intracel-

lular calcium signaling. Following ischemic and excitotoxic injuries,

EP1 receptor activation exacerbates neuronal damage, whereas its

activation following intracerebral hemorrhage may play a protective

role. The goal of this study was to investigate translational potential of

EP1 receptor as a target for new therapeutics in a preclinical model of

traumatic brain injury (TBI).

The experiments were performed in wildtype (WT) and EP1 re-

ceptor knockout (EP1

-/-

) mice of two age groups using controlled

cortical impact (CCI). Neurological deficit scores (NDS) were as-

sessed at 24 and 48 h, and brain pathology at 48 h after injury using

immuno- and histochemistry.

CCI resulted in significant cortical lesions, hippocampal swelling and

neurological deficits compared to sham (craniotomy only). The NDS after

CCI were significantly higher in older mice (7-11mo) compared to young

adult animals (2-4 mo) in both WT and EP1

-/-

animals. Post-treatment

with a selective antagonist, SC-51089, or an agonist, 17-pt-PGE

2

, had no

significant effect on cortical lesions and hippocampal swelling in young

adult WT mice. SC-51089 has also no effect on the NDS impaired after

CCI, whereas 17-pt-PGE

2

improved NDS at 24 h in WT but not in EP1

-/-

mice. Immunohistochemistry revealed CCI-induced gliosis (GFAP) and

microglial activation (Iba1) in selected ipsilateral brain regions which

This preclinical study provides, for the first time, clarification on

the respective role of EP1 receptor as a potential therapeutic target for

treatment of TBI. The results suggest that EP1 receptor is differen-

tially and age-dependently involved in neuroinflammatory pathways

associated with the progression of neurological and anatomical defi-

cits, and selective EP1 ligands could be used in the clinic for treatment

of certain neurological conditions following acute brain injuries.

Key words

controlled cortical impact, EP1 receptor, G-protein-coupled receptors,

knockout mice

D1-22

BENEFITS OF EARLY ADMINISTRATION OF LEVETIR-

ACETAM AFTER CONTROLLED CORTICAL IMPACT IN

RATS: OPERATION BRAIN TRAUMA THERAPY

Browning, M.

1,2

, Yan, H.Q.

1,3

, Poloyac, S.

1,4

, Dixon, C.E.

1,3

, Empey,

P.E.

1,4

, Jackson, T.K.

1,2

, Brockman, E.

1,2

, Ma, X.

1,3

, Janesko-Feldman,

K.

1,2

, Henchir, J.

1,3

, Vagni, V.

1,2

, Kochanek, P.M.

1,2

1

Safar Center, Pittsburgh, USA

2

Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA

3

Neurological Surgery, University of Pittsburgh, Pittsburgh, USA

4

University of Pittsburgh School of Pharmacy, Pittsburgh, USA

Operation Brain Trauma Therapy (OBTT), a multi-center pre-

clinical drug and biomarker screening consortium that evaluates

TBI therapies, selected levetiracetam as its fifth medication. De-

spite limited preclinical TBI studies, levetiracetam emerged as a

candidate given its sporadic clinical use treating posttraumatic

seizures and favorable safety profile. Levetiracetam’s proposed

benefit in TBI (potentiation of GABAergic and calcium channel

inhibition) may confer anti-convulsant, anti-excitotoxic, and other

benefits. We assessed the efficacy of a single 15min post-injury IV

dose (54 or 170mg/kg) on neurobehavioral/neuropathological out-

comes after CCI. After randomization into 4 groups (Sham, TBI

vehicle, TBI low dose, TBI high dose), 40 male Sprague-Dawley

rats underwent CCI (4m/s, 2.5-mm deformation) or sham surgery

followed 15min later by IV levetiracetam/vehicle administration.

Motor function (beam-balance/beam-walk) was assessed on d1-5

and Morris water maze (MWM) (acquisition/probe trial) on d14-

20. Rats were sacrificed on d21 to assess lesion volume/hemi-

spheric tissue loss. After TBI, beam-balance testing improved with

high but not low dose treatment (p

<

0.05 vs vehicle). On beam-

walk, all groups performed worse than sham (p

<

0.05). Average

latency to find the hidden platform on MWM increased in vehicle

and high dose groups after TBI, but not low dose. Probe trial

performance did not differ between groups. Levetiracetam mark-

edly reduced hemispheric tissue loss (p

<

0.05, high dose vs. ve-

hicle). Early single-dose IV levetiracetam produced benefits across

outcomes after CCI. Given the failure of other agents in OBTT, our

data and promising findings by the consortium suggest the need for

evaluation of dose optimization and therapeutic window for leve-

tiracetam, and potential for clinical translation. Support

:

US Army,

W81XWH-10-1-0623; T32-HD040686

Key words

anti-convulsant, controlled cortical impact, outcome, rat

D1-23

SPATIAL MEMORY NORMALIZATION AFTER TREAT-

MENT WITH ANATABINE BEGINNING 9 MONTHS AFTER

REPETITIVE MILD TBI

Ferguson, S.A.

1,2

, Mouzon, B.

1,2

, Abdullah, L.

1

, Crynen, G.

1

, Mathura,

V.

1

, Mullan, M.

1,2

, Crawford, F.

1,2

1

Roskamp Institute, Sarasota, USA

2

James A. Haley Veteran’s Hospital, Tampa, USA

TBI is a serious illness with long term consequences, even after mild

injuries, which involve chronic neuroinflammatory and neurode-

generative pathways. Previously we reported on the potential of

anatabine to affect neuroinflammation and improve memory when

taken acutely after TBI. We have continued to characterize anata-

bine’s effects in a crossover study as a continuation of our previous

work.

We previously presented significant improvements in spatial

memory and pathological outcome after treatment with anatabine

beginning acutely after repetitive mild TBI (r-mTBI). In the pre-

vious study, we treated mice orally with anatabine, administered in

their water throughout the study starting 30 minutes after r-mTBI

or r-sham. Untreated mice (both r-sham and r-mTBI) received

regular water. Although we did not see a significant improvement

A-108