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Hua Su Professor

Impact of Bone Fracture on Stroke Recovery. Hua Su Professor Center for Cerebrovascular Research, Departments of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA. Background. Stroke is the leading cause of disability in adults and an

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Hua Su Professor

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  1. Impact of Bone Fracture on Stroke Recovery Hua Su Professor Center for Cerebrovascular Research, Departments of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.

  2. Background • 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. Sennerby, JAMA, 2009 Kanis, Stroke, 2001 Lakshminarayan, Stroke, 2011

  3. Tibia fracture increase systemic and hippocampus inflammation and resulted in cognitive decline Terrando et al. PNAS, 2010

  4. Bone fracture after stroke D3 D0 D1 Behavior training (4 days) Behavioral test Sample collection Bone fracture pMCAO

  5. Adhesive removal test 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. Bouet, et al, Nature protocol,2009

  6. Corner test 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). Zhang, et al, Journal of Neuroscience, 2002

  7. Tibia fracture one day after pMCAO increased neuroinflammation and behavioral dysfunction Degos, et al, Anesthesiology, 2012

  8. Tibia fracture one day after pMCAO increased neuronal injury Degos, et al, Anesthesiology, 2012

  9. Depletion of macrophage reduces the negative impact of bone fracture on stroke injury Degos, et al, Anesthesiology, 2012

  10. Bone fracture before stroke

  11. Tibia fracture 6 hours or one day before pMCAO increased neuronal injury

  12. Tibia fracture 6 hours or one day before pMCAO increased neuroinflammation

  13. Tibia fracture 6 hours or one day before pMCAO increased behavioral dysfunction

  14. Bone fracture exacerbates stroke injury through enhance inflammation . . . . . . . . . . . . . . . . . . Bone fracture Macrophages activation Border zone 3 . Toxic processes 4 Unknown alarmins Core 1 activation Degos, et al, Anesthesiology, 2012 5 chemokines HMGB1 Healing stroke lesion 2 Macrophages

  15. Cholinergic inflammation resolving Pathway Su et al. Molecular Medicine, 2012

  16. Design PHA (PHA568487): α7 agonist MLA (methyllycaconitine): α7 antagonist

  17. Experimental design Han et al. Journal of Neurochemistry, 2014

  18. Activation of a-7 nAchR reduces behavioral deficits Han et al. Journal of Neurochemistry, 2014

  19. Activation of a-7 nAchR reduces reduced infarct volume and apoptotic neurons Han et al. Journal of Neurochemistry, 2014

  20. Activation of a-7 nAchR decreased microglia/macrophages in the peri-infarct region Han et al. Journal of Neurochemistry, 2014

  21. Activation of a-7 nAchR decreased reduced M1 and increased M2 marker gene expression Han et al. Journal of Neurochemistry, 2014

  22. Activation of a-7 nAchR increased anti-oxidant gene expression and reduced NADPH oxidase Han et al. Journal of Neurochemistry, 2014

  23. Activation of a-7 nAchR reduced nuclear factor kappa b (NF-kb) activity Han et al. Journal of Neurochemistry, 2014

  24. Summary Reduce brain injury α-7nAchRagonist (PHA568487) microglia/ macrophages M1/M2 M1 M1/M2 + Increase brain injury M2 oxidativestress anti-oxidativegene oxidativegene Han et al. Journal of Neurochemistry, 2014

  25. Summary 1. Bone fracture shortly before or after stroke increase stroke related neuronal injury through enhance inflammation. 2. Activation of a7 nAChR improves ischemic stroke recovery and reduces the adverse effect of bone fracture on stroke recovery through inhibition of inflammation and oxidative stress

  26. Thank You Espen Walker Wanqiu Chan Eunjung Choi Fanxia Shen Yi Guo Lei Mao Marine Camus Mamta Wankhede Vencent Dego Zhengyi Han Yue He Cameron McDougall Liang Wang Shuai Kang Lei Zhan Wan Zhu Rui Zhang Dingquan Zou Chen Bao Ethan Winkler Alireza Sadighi Zhao Li Funding: NIH AHA Michael Ryan Zodda Foundation

  27. Anti-inflammation • 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 a7 subunit-containing nAChRs. Borovikova et al. Nature, 2000 Bernik et al. J. Vasc. Surg. 2002 Wang et al. Nature, 2003 Ay et al. Brain Research, 2011 Han et al. PLOS One, 2014

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