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Hua SuProfessor
Center for Cerebrovascular Research, Departments of Anesthesia and Perioperative Care, University of
California, San Francisco, California, USA.
Impact of Bone Fracture on Stroke Recovery
1. Stroke is the leading cause of disability in adults and an important risk factor for bone fracture. In the United States, approximately 70,000 stroke victims suffer from bone fracture within the first year after their stroke.
2. Alternatively, stroke is one of the most devastating complications of bone fracture. About 0.2% to 4.1% patients suffer from stroke after hip surgery.
3. The impact of bone fracture on stroke recovery has not been fully studies.
Background
Sennerby, JAMA, 2009 Kanis, Stroke, 2001Lakshminarayan, Stroke, 2011
Tibia fracture increase systemic and hippocampus inflammation and resulted in cognitive decline
Terrando et al. PNAS, 2010
pMCAO
D0
Bone fracture
D1 D3
BehavioraltestSamplecollection
Behavior training (4 days)
Bone fracture after stroke
Adhesive removal test
Bouet, et al, Nature protocol,2009
Adhesive tape (0.3 X 0.3 cm) was applied on each paw of the mouse. The time was recorded with a maximum testing time of 120 seconds when the tapes were removed from each paw.
Corner test
Zhang, et al, Journal of Neuroscience, 2002
When mice come near the corner, both sides of their vibrissae are stimulated. The mice will rear forward and upward, then turn back to face the open end. Normal mice would turn to the left or right side with equal frequency, whereas the stroke mice would turn more frequent to the lesion side (left).
Tibia fracture one day after pMCAO increased neuroinflammation and behavioral dysfunction
Degos, et al, Anesthesiology, 2012
Tibia fracture one day after pMCAO increased neuronal injury
Degos, et al, Anesthesiology, 2012
Degos, et al, Anesthesiology, 2012
Depletion of macrophage reduces the negative impact of bone fracture on stroke injury
Bone fracture before stroke
Tibia fracture 6 hours or one day before pMCAO increased neuronal injury
Tibia fracture 6 hours or one day before pMCAO increased neuroinflammation
Tibia fracture 6 hours or one day before pMCAO increased behavioral dysfunction
Bone fracture
Border zone
...
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.. .
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...
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Healing stroke lesion
Macrophages
Core
Toxic processes
chemokines
Unknown alarmins
Macrophages activation
acti
vati
on
1
2
3
4
5HMGB1
Bone fracture exacerbates stroke injury through enhance inflammation
Degos, et al, Anesthesiology, 2012
Cholinergic inflammation resolving Pathway
Su et al. Molecular Medicine, 2012
Design
Group dose note label
Saline
PHA0.4 mg/kg Injection 1 time PHA-L
0.8 mg/kg Injection 1 time PHA-H1
0.8 mg/kg Injection 2 times PHA-H2
MLA4 mg/kg Injection 1 time MLA-L
6 mg/kg Injection 1 time MLA-H1
6 mg/kg Injection 2 times MLA-H2
PHA (PHA568487): α7 agonistMLA (methyllycaconitine): α7 antagonist
Experimental design
Han et al. Journal of Neurochemistry, 2014
Han et al. Journal of Neurochemistry, 2014
Activation of -7 nAchR reduces behavioral deficits
Han et al. Journal of Neurochemistry, 2014
Activation of -7 nAchR reduces reduced infarct volume and apoptotic neurons
Han et al. Journal of Neurochemistry, 2014
Activation of -7 nAchR decreased microglia/macrophages in the peri-infarct region
Han et al. Journal of Neurochemistry, 2014
Activation of -7 nAchR decreased reduced M1 and increased M2 marker gene expression
Han et al. Journal of Neurochemistry, 2014
Activation of -7 nAchR increased anti-oxidant gene expression and reduced NADPH oxidase
Han et al. Journal of Neurochemistry, 2014
Activation of -7 nAchR reduced nuclearfactor kappa b (NF-kb) activity
oxidative stress
microglia/macrophages
α-7 nAchR agonist(PHA 568487)
anti-oxidative geneoxidative gene
+
Incr
ea
se
bra
in in
jury
M1/M2
M1
M2
M1/M2
Reduce brain injury
Summary
Han et al. Journal of Neurochemistry, 2014
1. Bone fracture shortly before or after stroke increase stroke related neuronal injury through enhance
inflammation. 2. Activation of 7 nAChR improves ischemic stroke
recovery and reduces the adverse effect of bone fracture on stroke recovery through inhibition of inflammation and oxidative stress
Summary
Thank You
Lei ZhanWan ZhuRui ZhangDingquan Zou
Chen Bao
Ethan Winkler
Alireza Sadighi
Zhao Li
Funding:NIH AHAMichael Ryan Zodda Foundation
Espen WalkerWanqiu ChanEunjung ChoiFanxia ShenYi GuoLei MaoMarine CamusMamta WankhedeVencent DegoZhengyi HanYue HeCameron McDougallLiang WangShuai Kang
• Vagus nerve stimulation reduces infarct size in rat and mouse focal cerebral ischemia
• Cholinergic anti-inflammatory pathway inhibits cytokine release through a mechanism that requires the 7 subunit-containing nAChRs.
Anti-inflammation
Borovikova et al. Nature, 2000Bernik et al. J. Vasc. Surg. 2002Wang et al. Nature, 2003Ay et al. Brain Research, 2011Han et al. PLOS One, 2014
