Transition in Chronic Illness - Fatigue - Chronic Pain Australia
The Role of Neuroinflammation in Chronic Illness Keith W ...€¦ · Chronic Illness Keith W....
Transcript of The Role of Neuroinflammation in Chronic Illness Keith W ...€¦ · Chronic Illness Keith W....
The Role of Neuroinflammation in Chronic Illness
Keith W. Kelley, ProfessorIntegrative Immunology and Behavior Program
“…international, interdisciplinaryjournal devoted to investigation of the physiologicalsystems that integrate behavioral and immunologicalresponses.”
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 97 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 97 of 248
‐ I like to ride the Blue Line of the Boston Subway?
‐ I like to eat shell fish?
‐ I have nothing better to do?
‐ I like to have dinner with a former post‐doc at Harvard?
‐ I have published some stuff on neuroinflammation?
‐ I enjoy flying through Chicago O’Hare?
Question Answer
Why Am I Here at the Research Advisory Committee on Gulf War Veterans’ Illness?
No
No
No
Maybe
Yes
Yes
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 98 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 98 of 248
Summary of Research Advisory Committee on GWI, November 3, 2008
“Since 1994, ..expenditures of $440 million as GWI research.”
“The biological basis for GWI is unknown, and there is no efficacious treatment.”
“GWI research effort has yet to provide tangible results… Few treatments have been studied and none have been shown to providesignificant benefit for…ill veterans.”
“The 200,000 veterans with GWI complain of diffuse pain, headaches, difficulties in learning and memory, mood changes and unrelenting fatigue.”
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 99 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 99 of 248
What do I Want you to Remember?
Hypothesis from RAC Report:
“…neurotoxic Gulf War exposures may activate inflammatory processes in the brain and that increased brain levels of proinflammatory cytokines can produce a complex of multiple symptoms similar to GWI.”
Take Home Message:
Given the lack of treatments for GWI, the neuroinflammation hypothesis is worth testing because FDA-approved drugs to reduce neuroinflammation and pre-clinical animal research models are available.
Minimal Requirements for Neuroinflammation
- Microglial activation (ramified to ameboid, MHC-II, NFκβ)
- Pro- and anti-inflammatory cytokine synthesis
- Cox-1 & -2, iNOS
- Activation by peripheral immune signals
- No neutrophil or monocyte recruitment
- Neuronal dysfunction that does not require neuronal death
- Behavioral changes
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 100 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 100 of 248
The Experience of Just Being Sick:
Why do we feel sick and behave in a sick way when we are ill?
(Kent et al, 1992, TIPS, 13:24)
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 101 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 101 of 248
IL-1β
IP
Operant responding for food(Fixed ratio 10)
Social exploration of a juvenile
Exogenous IL‐1 into the Brain Causes Sickness Behaviors
Kent et al, Proc. Natl. Acad. Sci. 1992, 89:9117
The Sickness-Inducing Properties of Peripheral IL-1 are Mediated Centrally
IL-1β IL-1ra
Kent et al, Proc. Natl. Acad. Sci. 1992, 89:9117
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 102 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 102 of 248
Cytokines in the Periphery Act in the Brain
(Kent et al, 1992, TIPS, 13:24)
Measurement of pain sensitivity
Mechanical sensitivityVon Frey test
Laser beam
Heat sensitivityHargreaves test
Glass Mesh
Threshold forceWithdrawal; latency
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 103 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 103 of 248
“Fatigue: See How They Run, See How They Run”
They are not blind, just blinded from view due to HIPAA!
0
50
100
150
200
250
Perf
orm
ance
(Sec
onds
)
WT IL-10KO
57%
Motor Coordination(Rotarod)
0
50
100
150
200
Tim
e to
Fat
igue
(min
)
WT IL-10KO
85%43%
Exhaustive Fatigue(Treadmill)
0
20
40
60
80
100
Fold
cha
nge
WT IL-10KO
60%
IL-1β mRNA inCerebellum
Fatigue and Deficits in Motor Coordination Induced by LPS are Exacerbated in IL‐10 Knockout Mice
Saline LPS
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 104 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 104 of 248
100150200250300350400
1 2 3 4 5 6 7 8100150200250300350400
1 2 3 4 5 6 7 8Test Day
Dis
tanc
e Sw
am (c
m)
old
young
0
140180
220260300
old youngD
ista
nce
Swam
(cm
)
*SalineLPS
Chen et al., 2008Brain, Behavior & Immunity 22:301-311
LPS Disrupts Spatial-Working Memory in Old but not Young Mice
Distance SwamWorking memory Saline or LPS
Days 1-8 (acquisition phase) Day 9
4 h
Working memory
24-m
3-m
24-m
3-m
• ?• Loss of interest / anhedonia• Cognitive disturbances• ?• ?• Altered sleep pattern• Anorexia• Reduced locomotor activity • Lethargy
• Depressed mood• Loss of interest / anhedonia• Decreased concentration • Worthlessness or guilt• Suicidal thoughts• Insomnia / hypersomnia• Changes in appetite / weight• Agitation / slowing• Fatigue / anergia
Major Depressive Episode(DSM-IV)
Sickness Behavior
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 105 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 105 of 248
IDOIFNγ/TNFα
Bacillus Calmette-Guérin
Sickness and Depressive-like
Behaviors
Pre‐Clinical Model of Depressive‐Like Behaviors
Inhibitor of IDO (1‐Methyl Tryptophan) Blocks BCG‐induced Depressive‐Like Behavior (7d)
O’Connor et al., J Immunol. 2009.182:3202‐3212
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 106 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 106 of 248
2
4
6
8
IFN
-γΔ
mR
NA
Sal Mino
**
2
4
6
8
IFN
-γΔ
mR
NA
Sal Mino
**
5
10
15
20
TNF-αΔ
mR
NA
Sal Mino
5
10
15
20
TNF-αΔ
mR
NA
5
10
15
20
TNF-αΔ
mR
NA
Sal Mino
5
10
15
20
IL-1βΔ
mR
NA
Sal Mino
5
10
15
20
IL-1βΔ
mR
NA
5
10
15
20
IL-1βΔ
mR
NA
Sal Mino
**
**
nd nd10
30
50
70
IDOΔ
mR
NA
(x10
)
MinoSal
nd nd10
30
50
70
IDOΔ
mR
NA
(x10
)
MinoSal
SalineLPSSalineLPS**
Minocycline Reduces LPS‐Induced Pro‐inflammatory Cytokines in the Brain
O’Connor et al, Mol. Psychiatry. 2008. 14:511‐522
40
80
120
160
MinoSal
FST I
mmob
ility
(s) Sal
LPS
**
40
80
120
160
MinoSal
FST I
mmob
ility
(s) Sal
LPSSalLPS
**
SalLPS
0
100
200
300
TST
Immob
ility
(s)
MinoSal
** SalLPSSalLPS
0
100
200
300
TST
Immob
ility
(s)
MinoSal
**
Minocycline Blocks Induction of LPS‐Induced Depressive‐like Behaviors
O’Connor et al, Mol. Psychiatry. 2008. 14:511‐522
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 107 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 107 of 248
Digler and Johnson, 2008. J. Leukocyte Biology 84:932‐939
The Microglial Scar Hypothesis in Gulf War Illness
Altered microglial phenotype (primed
microglia)
T2: Reactivation by psychosocial stressors and/or banal infection
More intense and longer lasting
neuroinflammatory response
Symptoms of sickness
T1: Original insult (e.g., combined
exposure to pyridostigmine bromide
and pesticides)
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 108 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 108 of 248
-Antibiotics (Minocycline)
-New Drugs for Fibromyalgia (e.g., SNRI milnacipran)
-Botanicals (turmeric, resveratrol, luteolin)
- HMG-CoA reductase inhibitors (statins)
- Diet - Soluble Fiber like Pectin
- IDO Inhibitors now in Phase I clinical trials
-Exercise
Potential Existing FDA‐Approved Approaches for Neuroinflammation in Gulf War Illness
SummaryNeuroinflammation in Pre-Clinical
Animal Models
-Reduces Appetite and Motivation
-Increases Exhaustive Fatigue (Mental Fatigue?)
-Increases Sensitivity to Pain
-Causes Deficits in Learning and Memory
-Induces Depressive-Like Behaviors
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 109 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 109 of 248
What do I Want you to Remember?
Hypothesis from RAC Report:
“…neurotoxic Gulf War exposures may activate inflammatory processes in the brain and that increased brain levels of proinflammatory cytokines can produce a complex of multiple symptoms similar to GWI.”
Take Home Message:
Given the lack of treatments for GWI, the neuroinflammation hypothesis is worth testing because FDA-approved drugs to reduce neuroinflammation and pre-clinical animal research models are available.
Bordeaux team:Nathalie CastanonLucile CapuronJacques LestageMaite Moreau
Urbana team:Caroline AndreRobert DantzerJonathan GodboutKeith W. KelleyMarc LawsonJason O’ConnorXun FuYun Xia
Appendix Presentation 5 - Kelley
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 110 of 248
RAC-GWVI Meeting Minutes June 29-30, 2009 Page 110 of 248