Hua Su Professor Center for Cerebrovascular Research, Departments of Anesthesia and Perioperative...

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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.

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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