Page 141 - NNS 2014 Program & Abstract Book

to the neurobehavioral outcomes at acute timepoints, at a chronic
timepoint 6 months after injury we saw a significant improve-
ment of spatial memory of the anatabine treated r-mTBI mice
compared to untreated r-mTBI mice, with anatabine treated r-
mTBI mice performing as well as r-sham mice. At 9 months, 4 mice
per group were euthanized, revealing regionally-specific reduc-
tions in IBA1 and GFAP staining in the anatabine treated r-mTBI
mice.
We have continued to characterize the surviving mice using a
crossover study. Both r-mTBI and r-sham mice that were previously
untreated were given anatabine starting at the 9 month timepoint.
Mice that previously received anatabine began receiving regular water
only. The mice were re-evaluated using the Barnes maze at 12 and 18
months post-injury. Although r-mTBI mice that began taking anata-
bine at 9 months post-TBI initially continued to perform worse than
shams at the 12 month timepoint, by 18 months there were no sig-
nificant differences in spatial memory between any group. Anatabine
shows potential at improving memory following TBI, mitigating
against pathogenic neuroinflammation, and may have a long thera-
peutic window.
Key words
neuroinflammation, neuroprotection, TBI
D1-24
ACUTE OVER-THE-COUNTER PHARMACOLOGICAL IN-
TERVENTION DOES NOT ADVERSELY AFFECT BEHA-
VIORAL OUTCOME FOLLOWING DIFFUSE TRAUMATIC
BRAIN
Harrison, J.L.1–3, Rowe, R.K.1,2,4, O’Hara, B.F.5 , Adelson, P.D.1,2,
Lifshitz, J.1,2,4
1BARROW Neurological Institute at Phoenix Children’s Hospital,
Phoenix, USA
2University of Arizona COM-Phoenix, Child Health, Phoenix, USA
3Arizona State University, Neuroscience, Tempe, USA
4Veteran Affairs Healthcare System, Phoenix, USA
5University of Kentucky, Biology, Lexington, USA
Following mild traumatic brain injury (TBI), patients may self-treat
symptoms of concussion, including post-traumatic headache, tak-
ing over-the-counter (OTC) analgesics. Administering one dose of
OTC analgesics immediately following experimental brain injury
mimics the at-home treated population of concussed patients and
may accelerate the understanding of the relationship between
brain injury and OTC pharmacological intervention. In the current
study, we hypothesize that acute administration of OTC analge-
sics following experimental diffuse TBI in the mouse will attenuate
the functional consequences of TBI by modulating inflammatory
responses.
Adult, male C57BL/6 mice were subjected to midline fluid percus-
sion (mFPI) injury (1.4 atm). Experimental groups included mFPI
paired with either ibuprofen (60 mg/kg, i.p.; n = 16), acetaminophen (40
mg/kg, i.p.; n = 9), or vehicle (15% ethanol (v/v) in 0.9% saline; n = 13)
and sham injury paired OTC medicine or vehicle (n = 7-10 per group).
At 24 hrs after injury, functional outcome was assessed using the ro-
tarod task and a modified neurological severity score (NSS). Cortical
cytokine levels were measured by multiplex ELISA at 6 hrs or 24 hrs
post-injury to evaluate pharmacological effect on acute inflammation.
TBI significantly impaired motor performance as indicated by la-
tency to stay on the rotarod (F(3,53) = 3.688, p = 0.0174). Significant
neurological impairments were detected between groups as mea-
sured by modified neurological severity score (KW(4, 57) = 27.37,
p < 0.001). Pharmacological intervention did not attenuate or exacer-
bate TBI-induced functional deficits. Six hours post-injury, brain in-
jury increased cortical pro-inflammatory cytokines IL-6 (F(1,30) =
4.468, p = 0.0430) and TNF-a (F(1,30) = 6.853, p = 0.0137). However,
levels were not affected by pharmacological intervention at 6 hrs or
24 hrs post-injury. These data indicate that acute administration of
OTC analgesics did not exacerbate or attenuate brain-injury deficits
which may inform clinical recommendations for the at-home treated
mildly concussed patient.
NIH R21-NS072611
Key words
analgesic, behavior, inflammation, TBI
D1-25
REMOTE ISCHEMIC CONDITIONING AS PRE-HOSPITAL
THERAPEUTIC INTERVENTION FOR DIFFUSE TRAU-
MATIC BRAIN INJURY
Harrison, J.L.1–3, Rowe, R.K.2–4, Morganti-Kossmann, M.C.2,3,
Adelson, P.D.2,3, Lifshitz, J.L.2–4
1Arizona State University, Neuroscience, Tempe, USA
2University of Arizona COM, Phoenix, USA
3BARROW Neurological Institute at Phoenix Children’s Hospital,
Phoenix, USA
4Veteran Affairs Healthcare System, Phoenix, USA
Transient ischemia in the rat hindlimb – remote ischemic conditioning
(RIC) – has shown neuroprotective effects following experimental
stroke through indeterminate mechanisms. Traumatic brain injury
(TBI) and stroke share secondary injury processes including inflam-
mation and lipid peroxidation. This study seeks to evaluate the ther-
apeutic potential of RIC following experimental diffuse TBI. We
hypothesize that RIC will decrease neuropathology associated with
diffuse TBI through modulation of inflammation and lipid peroxida-
tion pathways.
Adult male sprague-dawley rats were trained on rotarod, beam
balance, and beam walk tasks three consecutive days followed by one
baseline test immediately prior to surgery. Rats were then subjected to
moderate midline fluid percussion brain injury (2.0 atm) or sham
injury. One hour later, rats were returned to isoflurane anesthesia and
a tourniquet was applied to one hindlimb of RIC rats as proximally as
possible, tightened until absence of pulse in the hindpaw, and re-
moved after 60 minutes. Non-RIC rats received only anesthesia.
Plasma was collected from all groups 6 h post-injury for analysis of
cytokine levels by multiplex ELISA. Motor function was evaluated
using trained tests on days 1, 3, 5, 7 post-injury. Brains were collected
7 d post-injury for histochemical analysis of TBI-associated neuro-
pathology via silver stain and immunohistochemical markers of in-
flammation and lipid peroxidation.
RIC groups performed equivalently to non-RIC groups on tests of
motor function including rotarod (F(1,17) = 2.126, p = 0.1630), beam
balance (F(1,20) = 0.2659, p = 0.6117), and beam walk (F(1,20) =
0.2296, p = 0.6370). Thus, the RIC paradigm is a convenient, non-
invasive method for inducing transient ischemia without neuromotor
dysfunction. Ongoing analysis of biochemical and histological end-
points will determine efficacy of RIC to reduce neuropathological
consequences of TBI. Ultimately, RIC could serve as cost-effective
and feasible early intervention for TBI.
Diane and Bruce Halle Foundation
Key words
behavior, histology, ischemic conditioning, TBI, therapy
A-109