Page 115 - NNS 2014 Program & Abstract Book

markers associated with inflammatory response and macrophage
polarization. Our data show that genetic deletion of CX3CR1 or
CCR2 differentially affects the expression of various inflamma-
tory and macrophage polarization markers. These data may suggest
that selectively targeting distinct populations of infiltrating mono-
cytes could differentially affect the TBI-induced inflammatory
response.
Funding
This work was supported by the NIH R01 CA133216 (S.R.), R21
AG042016 (S.R.), and Alzheimer Association IIRG-11-202064 (S.R.)
Key words
CCR2, CX3CR1, hippocampus, polarization
C2-19
PDE4B INHIBITION RESCUES CHRONIC MEMORY DEFI-
CITS FOLLOWING TRAUMATIC BRAIN INJURY
Titus, D.J.1, Furones, C.1 , Galea, B.J.1, Dietrich, W.D.1, Gurney, M.E.2,
Atkins, C.M.1
1University of Miami Miller School of Medicine, Miami, FL, USA
2Tetra Discovery Partners, Grand Rapids, MI, USA
Learning and memory deficits are the most common neurocognitive
consequences associated with chronic traumatic brain injury (TBI),
but poorly understood from a mechanistic viewpoint. Our previous
study has shown that a pan-phosphodiesterase 4 (PDE4) inhibitor
rescues cognitive deficits following TBI. However, pan-PDE4 in-
hibitors are hampered by unwanted side effects and the develop-
ment of more isoform-selective inhibitors would greatly improve
translational development. We have found that TBI induces ex-
pression of the subfamily isoform PDE4B2. Thus, we hypothesized
that treating animals with a subtype-specific PDE4B inhibitor could
reverse the cognitive deficits induced by TBI. To test this hy-
pothesis, adult male Sprague Dawley rats received sham surgery or
moderate parasagittal fluid-percussion brain injury. After 3 months
of recovery, animals were treated with the selective PDE4B in-
hibitor A33 prior to cognitive training. Animals were trained in cue
and contextual fear conditioning, spatial reference memory and
spatial working memory.
TBI-induced deficits in cue and contextual fear conditioning were
significantly reversed with A33 treatment. Furthermore, hippocampal-
dependent spatial memory was enhanced in TBI animals treated with
A33 as compared to TBI animals treated with vehicle. Additionally,
administration of A33 was also effective in rescuing working memory
performance in TBI animals and restored their performance to non-
injured levels. To further understand the underlying mechanisms of
these memory impairments, basal synaptic transmission and hippo-
campal long-term potentiation (LTP) of the Schaffer collateral path-
way in area CA1 were studied 3 months after TBI or sham surgery.
Hippocampal slices from TBI animals showed a significant reduction
in basal synaptic transmission and impairment in expression of LTP as
compared to sham surgery animals. We are currently analyzing the
effects of A33 on these electrophysiological changes. These results
indicate that a subtype-selective PDE4B inhibitor may be a potential
cognitive enhancer and reverse chronic cognitive dysfunction fol-
lowing TBI.
Supported by: The Miami Project to Cure Paralysis, NIH/NINDS
NS056072 and NIH/NINDS NS069721
Key words
fluid-percussion injury, learning and memory, phosphodiesterase 4B,
synaptic plasticity
C2-20
EFFECTS OF PROPHYLACTIC OMEGA-3 FATTY ACID
TREATMENT ON TBI-INDUCED MICRORNA EXPRESSION
Weisz, H., Boone, D., Sell, S., Parsley, M., Bolding, I., Dewitt, D.,
Prough, D., Hellmich, H.
University of Texas Medical Branch, Galveston, TX, USA
Psychiatric co-morbidities, such as depression, often develop after
traumatic brain injury (TBI) and exacerbate the diminished quality
of life and disability caused by the trauma. Preliminary studies
suggest that TBI-induced changes in microRNA (miRNA) expres-
sion may increase the risk of developing depression. Recent reports
indicate that prophylactic treatment with omega-3 polyunsaturated
fatty acids (x-3 PUFAs) ameliorates both injury severity and cog-
nitive decline in animal models by acting as a neuroprotective agent.
In humans, a deficiency in dietary x-3 PUFAs may cause or worsen
depression, whereas supplementation with x-3 PUFAs may relieve
depressive symptoms. We hypothesized that prophylactic treatment
with x-3 PUFAs will ameliorate the effects of TBI on miRNA ex-
pression. In our rodent model of fluid-percussion TBI, rats were
prophylactically dosed with x-3 PUFAs (Menhaden fish oil) in their
diet continuously four-weeks prior to the infliction of injury. Control
animals received a diet consisting of 7% by weight soybean oil
chow. Blood was collected from the jugular vein of all animals prior
to dietary dosing, 24 h before/after TBI, and 4-weeks after treatment.
Expression levels of circulating miRNAs were determined by
quantitative RT-PCR. Three weeks post-TBI, depression-like be-
havior (reduction in immobility time) of control and TBI animals
was assessed using the Forced Swim Test. At the conclusion of the
study, 4 weeks after TBI, animals were sacrificed for histopatho-
logical and molecular analysis by qPCR, which included miRNA
expression in laser-microdissected brain regions associated with
depression (i.e., hippocampus, nucleus accumbens, prefrontal cortex,
and suprachiasmatic nucleus). Examination of miRNA expression
levels in depression-related brain regions has provided compelling
evidence to suggest that TBI causes a dysregulation in miRNAs that
regulate genes associated with cell survival and cell death. A subset
of these miRNAs showed differential expression in serum samples
correlating with that of depression-associated brain regions. This
subset of circulating miRNAs might serve as a non-invasive bio-
marker of injury progression and effective prophylactic treatment in
human TBI patients.
Key words
cell survival, depression, microRNA, TBI
C2-21
PHOSPHODIESTERASE 4B INHIBITION AS A THER-
APEUTIC FOR TRAUMATIC BRAIN INJURY
Wilson, N.M.1, Furones, C.1, Gurney, M.E.2, Dietrich, W.D.1, Atkins,
C.M.1
1University of Miami Miller School of Medicine, Miami, USA
2Tetra Discovery Partners, Grand Rapids, USA
The neuroprotective benefits of cAMP elevation, via pan-PDE4
inhibition, have been used as a therapeutic strategy in many CNS
injury models, such as spinal cord injury (SCI), cerebral ischemia,
and traumatic brain injury (TBI). Knock-out studies have indicated
that the anti-inflammatory effects of pan-PDE4 inhibition are pri-
marily attributed to the PDE4B subfamily. Pro-inflammatory
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