traumatic brain injury and neuroinflammation/media/files/activity files/research...traumatic brain...
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Traumatic Brain Injury
and Neuroinflammation
Fiona Crawford, Ph.D. President and CEO, Roskamp Institute
Sarasota, Florida NAS, DC
032017
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• Major cause of death and disability
• Physical disabilities
• Neurological deficits
• Visual Dysfunction
• Memory problems
• Learning disabilities
• Personality changes
• Military and Civilian relevance
Consequences of TBI
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• Complex multi-modal disease process
• Structural and functional damage
• Primary Injury: • Immediate mechanical damage – neuronal/ glial
damage, contusion, hemorrhage, axonal sehearing
• Secondary Injury: • Cascades of molecular events – calcium homeostasis,
glutamate excitotoxicity, mitochondrial dysfunction,
free radical generation, apoptosis, neuroinflammation
TBI
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• Innate and adaptive immune responses
• Cytokines – IL1B, TNFa, IL18…..
• Chemokines – migration of neutrophils, attraction
of monocytes/macrophages, recruitment of T-
lymphocytes
• Activated macrophages and/or microglia
• Multiple activation phenotypes
• “M1-like vs M2-like”
TBI
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TBI From Loane & Kumar; Exp. Neurol. 2016
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{
Pathology: Mouse and Man
Myelin loss Inflammation Astrogliosis Axonal Injury
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TBI models used at Roskamp • CCI model of TBI in APPsw mouse model of Alzheimer’s
Disease (22mo old; moderate injury; 1 month timepoint), genomic analyses – significant differences in immune/inflammatory/cell death gene expression
• CCI in APOE transgenic mice (10mo; moderate injury; 1 month timepoint), genomic studies – significantly greater overall response in E3 versus E4 mice – immune/inflammatory/lipid
• CCI in APOE3 and APOE4 proteomic analyses (7mo old;
moderate and severe injury; 24hr/1month/3month timepoints) using iTRAQ – immune/inflammatory changes
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Other TBI models • Diversity of preclinical research - Blast, CCI, FPI, Weight
Drop, Rotational; animal age/genotype/gender; time of analysis – all demonstrate inflammation
• Closed head impact model of engineered rotational acceleration CHIMERA – 3 hits 24hr apart; Iba1 & GFAP at 6 months post-TBI Chen et al J Neurotrauma 2017
• CCI in wild type mice – Microglial activation at 24hrs post-
TBI; Microglial-derived microparticles mediating neuroinflammation after TBI; seeding capability – Kumar et al J Neuroinflammation 2017
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Incidence charts: DoD TBI Numbers
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Repetitive concussive injuries
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Animal model of TBI:
Electromagnetic impactor
Focal injury with a
5 mm tip
Modified CCI apparatus
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Roskamp mTBI model
• Closed head injury - 1mm depth midline hit
• no fracture, no bleed
• single hit (s-mTBI) and relevant sham (s-sham)repetitive hit (r-mTBI) - 5 hits with an inter-injury interval of 48 hrs - and relevant sham (r-sham)
• Neurobehavioral and neuropathological characterization to 24 months post-injury
Mouzon et al. 2012, 2014
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Persistent cognitive deficits in wild type mouse model of mild TBI
Mouzon et al. 2012, 2014
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White matter changes in wild type mouse model of mild TBI
12 months 6 months
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Progressive neuroinflammation - Iba1 in wild type mouse model of
mild TBI
r-sham r-mTBI
Acut
e
6 M
onth
s
12 M
onth
s
**
*** ***
*** *
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Progressive neuroinflammation - GFAP in wild type mouse model of
mild TBI A
cute
6
Mon
ths
12 M
onth
s
r-sham r-mTBI
***
*** ***
***
*
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Lifelong changes in GFAP – astrocyte activation - in wild type
mouse model of mild TBI
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Lifelong changes in Iba1 – microglial activation - in wild type
mouse model of mild TBI
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Progressive neuroinflammation – Phospho-STAT3
12 months post-r-mTBI 24 months post-r-mTBI
r-mTBI
r-sham
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Targeting Inflammation
Anatabine •Alkaloid derived from tobacco and
plants of solenaceae family
• 3 year history of safe use as a
dietary supplement
• Potent anti-inflammatory – inhibitor
of STAT3 and NFkB
• Efficacy in mouse models of AD,
EAE model of Multiple Sclerosis,
Tauopathy
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Acute effects of anatabine on
Barnes Maze performance in the r-mTBI model
0
5
10
15
20
25
Seco
nds Placebo Sham
Placebo TBIAnatabine ShamAnatabine TBI
*
Ferguson et al. 2017
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Chronic effects of anatabine on
Barnes Maze performance 6 mo. after r-mTBI
0
5
10
15
20
25
30
Seco
nds Sham PBS
TBI PBS
Sham RCP006
TBI RCP006
* * Sham Anatabine
TBI Anatabine
Ferguson et al. 2017
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Effects of anatabine on Iba1 staining 9 months after r-mTBI
Ferguson et al. 2017 0
0.5
1
1.5
2
2.5
Perc
ent A
rea
Corpus Callosum 9 Months Post-
*
0
2
4
6
8
10
Perc
ent A
rea
Hippocampus 9 Months Post-TBI PlaceboShamPlacebo TBI
AnatabineShamAnatabineTBI
*
**
**
TBI-Placebo
Sham-Placebo Sham-Placebo
TBI-Anatabine
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Effects of anatabine on
GFAP staining 9 months after r-mTBI
Ferguson et al. 2017
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Anatabine crossover at 9 mo after r-mTBI; Iba1 in CC at 18 mo
TBI-Placebo
Sham-Anatabine Sham-Placebo
TBI-Anatabine
Ferguson et al. 2017
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Delayed treatment with Anatabine mitigates microgliosis (Iba1)
Ferguson et al. J Neurotrauma 2017
0123456789
10
Perc
ent A
rea
Hippocampus 9 Months Post-TBI
Placebo Sham
Placebo TBI
Anatabine Sham
Anatabine TBI
*
**
**
0
5
10
15
20
25
Perc
ent A
rea
Hippocampus 18 Months Post-TBI
Sham Anatabine
TBI Anatabine
Sham Placebo
TBI Placebo
*
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Effects of anatabine on STAT3 after r-mTBI
9 months after r-mTBI
TBI-Plac. TBI-Anat.
Sham-Anat. Sham-Plac.
18 mo after r-mTBI (9mo after crossover)
TBI-Anat. TBI-Plac.
Sham-Anat. Sham-Plac.
12 months post-r-mTBI 24 months post-r-mTBI
r-mTBI
r-sham
Treatment naïve mice after r-mTBI/r-sham Quantification of p-STAT3 over time post-r-mTBI/r-sham
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Tau in TBI models
Published difficulties in recapitulating TBI-dependent
tau pathology in mouse models Variables influencing tau pathology in preclinical
models Nature of the injury – e.g. Goldstein 2012, Huber 2013 Site of the injury – e.g. Luo 2014 Severity of injury Frequency of injury – e.g. Petraglia 2014 Other injury paradigms Age at injury – existing pathology e.g. Ojo 2014
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Exploring additional r-mTBI paradigms
Same mild injury but administered in different paradigms Roskamp Chronic r-mTBI
2 hits/week for 2-3 months
Euthanasia at 6 months post-start of r-mTBI
paradigm
Relevant sham/anesthesia controls
hTau transgenic mice, 10 r-mTBI, 12 r-sham
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B C
D E
G H
A
F
Cortical Tau Immunoblotting
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Neuropathology in chronic r-mTBI
Ojo JNEN 2015
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Neuropathology quantification
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Mitigation of Tau pathology (PHF1)
in CD40-deficient P301S mice
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Conclusions
• Many variables influence TBI sequelae – • Nature and severity of injury, genotype, diet
• Inflammation represents a common denominator across all human TBI cases and all preclinical models of TBI
• Heterogeneity of human TBI • Requires investigation of multiple models of TBI
• The therapeutic window may be more favorable than
originally anticipated
• Anatabine show promise as a TBI therapeutic - much more preclinical work to do for effective clinical translation
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Conclusions & Future Directions
Targeting specific aspects of neuroinflammatory pathways with compounds demonstrating efficacy
in multiple preclinical models
Understanding the mechanisms responsible for the persistence of neuroinflammation after
TBI, and the timing and context of those responses, is critical to
development of TBI therapeutics
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Acknowledgements
Cillian Lynch, M.S. Venkat Mathura, Ph.D. Benoit Mouzon, Ph.D. Joseph Ojo, Ph.D. Daniel Paris, Ph.D. Alexander Morin, M.S. Rad Tzekov, M.D., Ph.D. Michael Mullan, M.D., Ph.D.
Laila Abdullah, Ph.D. Moustafa Algamal, M.S. Corbin Bachmeier, Ph.D. Gogce Crynen, Ph.D. Tanja Emmerich, Ph.D. Scott Ferguson, Ph.D. James Evans Carlyn Lungmus
Department of Defense, Veterans Administration, The Chronic Effects of Neurotrauma Consortium (CENC),
National Institutes of Health, Roskamp Foundation,
Dr. William Stewart, University Hospital, Glasgow; Dr. Elliott Mufson, Barrow Institute; Drs. Peter Davies & Chris Acker, Feinstein Institute; Dr. M Dretsch, National Intrepid CoE; Drs. R Richardson, R Vanderploeg, S Scott; Tampa VA