Stroke research at a crossroad: asking the brain for directions


Ischemic stroke remains a vexing public health problem. Although progress has been made in prevention and supportive care, efforts to protect the brain from ischemic cell death have failed. Thus, no new treatment has made it from bench to bedside since tissue plasminogen activator was introduced in 1996. The brain has a remarkable capacity for self-preservation, illustrated by the protective responses induced by ischemia, preconditioning and exercise. Here we describe the mechanisms underlying brain self-protection, with the goal of identifying features that could provide insight into stroke therapy. Unlike traditional therapeutic approaches based on counteracting selected pathways of the ischemic cascade, endogenous neuroprotection relies on coordinated neurovascular programs that support cerebral perfusion, mitigate the harmful effects of cerebral ischemia and promote tissue restoration. Learning how the brain triggers and implements these protective measures may advance our quest to treat stroke.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Protective pathways activated by cerebral ischemia.
Figure 2: Intracellular events leading to ischemic tolerance.
Figure 3: Local and remote mechanisms of endogenous neuroprotection.


  1. 1

    Roger, V.L. et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 123, e18–e209 (2011).

    Article  Google Scholar 

  2. 2

    Hachinski, V. et al. Stroke: working toward a prioritized world agenda. Stroke 41, 1084–1099 (2010).

    Article  Google Scholar 

  3. 3

    Fonarow, G.C. et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation 123, 750–758 (2011).

    CAS  Article  Google Scholar 

  4. 4

    Moskowitz, M.A., Lo, E.H. & Iadecola, C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198 (2010).

    CAS  Article  Google Scholar 

  5. 5

    Moskowitz, M.A. Brain protection: maybe yes, maybe no. Stroke 41, S85–S86 (2010).

    Article  Google Scholar 

  6. 6

    Kunz, A. & Iadecola, C. Cerebral vascular dysregulation in the ischemic brain. in Handbook of Clinical Neurology Vol. 92, Ch. 14, (eds. Vinken, P.J. and Bruyn, G.W.) 92, Ch. 14, 283–305 (2008).

  7. 7

    Iadecola, C. & Anrather, J. The immunology of stroke: from mechanisms to translation. Nat. Med. 17, 796–808 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Johansson, A., Ahrén, B., Näsman, B., Carlström, K. & Olsson, T. Cortisol axis abnormalities early after stroke—relationships to cytokines and leptin. J. Intern. Med. 247, 179–187 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Liebeskind, D.S. Reperfusion for acute ischemic stroke: arterial revascularization and collateral therapeutics. Curr. Opin. Neurol. 23, 36–45 (2010).

    Article  Google Scholar 

  10. 10

    Sharp, F.R., Bergeron, M. & Bernaudin, M. Hypoxia-inducible factor in brain. Adv. Exp. Med. Biol. 502, 273–291 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Dirnagl, U., Simon, R.P. & Hallenbeck, J.M. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 26, 248–254 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Paschen, W. Shutdown of translation: lethal or protective? Unfolded protein response versus apoptosis. J. Cereb. Blood Flow Metab. 23, 773–779 (2003).

    Article  Google Scholar 

  13. 13

    Hardingham, G.E. & Lipton, S.A. Regulation of neuronal oxidative and nitrosative stress by endogenous protective pathways and disease processes. Antioxid. Redox Signal. 14, 1421–1424 (2011).

    CAS  Article  Google Scholar 

  14. 14

    Yenari, M.A. Heat shock proteins and neuroprotection. Adv. Exp. Med. Biol. 513, 281–299 (2002).

    CAS  Article  Google Scholar 

  15. 15

    Greenberg, D.A. & Jin, K. Growth factors and stroke. NeuroRx 3, 458–465 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Torres-Aleman, I. Toward a comprehensive neurobiology of IGF-I. Dev. Neurobiol. 70, 384–396 (2010).

    CAS  PubMed  Google Scholar 

  17. 17

    Digicaylioglu, M. Erythropoietin in stroke: quo vadis. Expert Opin. Biol. Ther. 10, 937–949 (2010).

    CAS  Article  Google Scholar 

  18. 18

    Kitagawa, K. CREB and cAMP response element-mediated gene expression in the ischemic brain. FEBS J. 274, 3210–3217 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Clarkson, A.N., Huang, B.S., Macisaac, S.E., Mody, I. & Carmichael, S.T. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468, 305–309 (2010).

    CAS  Article  Google Scholar 

  20. 20

    Kernie, S.G. & Parent, J.M. Forebrain neurogenesis after focal ischemic and traumatic brain injury. Neurobiol. Dis. 37, 267–274 (2010).

    Article  Google Scholar 

  21. 21

    Zhang, Z.G., Zhang, L., Jiang, Q. & Chopp, M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ. Res. 90, 284–288 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Dirnagl, U., Becker, K. & Meisel, A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol. 8, 398–412 (2009).

    CAS  Article  Google Scholar 

  23. 23

    Saxena, P., Newman, M.A.J., Shehatha, J.S., Redington, A.N. & Konstantinov, I.E. Remote ischemic conditioning: evolution of the concept, mechanisms, and clinical application. J. Card. Surg. 25, 127–134 (2010).

    Article  Google Scholar 

  24. 24

    Kunz, A. et al. Neurovascular protection by ischemic tolerance: role of nitric oxide and reactive oxygen species. J. Neurosci. 27, 7083–7093 (2007).

    CAS  Article  Google Scholar 

  25. 25

    Pedersen, C.M. et al. Remote ischemic preconditioning prevents systemic platelet activation associated with ischemia-reperfusion injury in humans. J. Thromb. Haemost. 9, 404–407 (2011).

    CAS  Article  Google Scholar 

  26. 26

    Zhang, Y., Park, T.S. & Gidday, J.M. Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent survivin activation. Am. J. Physiol. Heart Circ. Physiol. 292, H2573–H2581 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Gesuete, R. et al. Glial cells drive preconditioning-induced blood-brain barrier protection. Stroke 42, 1445–1453 (2011).

    Article  Google Scholar 

  28. 28

    Andjelkovic, A.V., Stamatovic, S.M. & Keep, R.F. The protective effects of preconditioning on cerebral endothelial cells in vitro. J. Cereb. Blood Flow Metab. 23, 1348–1355 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Huang, S.S., Wei, F.C. & Hung, L.M. Ischemic preconditioning attenuates postischemic leukocyte–endothelial cell interactions: role of nitric oxide and protein kinase C. Circ. J. 70, 1070–1075 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Cotman, C.W., Berchtold, N.C. & Christie, L.-A. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 30, 464–472 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Endres, M. et al. Mechanisms of stroke protection by physical activity. Ann. Neurol. 54, 582–590 (2003).

    Article  Google Scholar 

  32. 32

    Llorens-Martín, M., Torres-Alemán, I. & Trejo, J.L. Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour. Mol. Cell. Neurosci. 44, 109–117 (2010).

    Article  Google Scholar 

  33. 33

    Gómez-Pinilla, F., Dao, L. & So, V. Physical exercise induces FGF-2 and its mRNA in the hippocampus. Brain Res. 764, 1–8 (1997).

    Article  Google Scholar 

  34. 34

    Zaheer, A. et al. GMF-knockout mice are unable to induce brain-derived neurotrophic factor after exercise. Neurochem. Res. 31, 579–584 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Zhang, F., Wu, Y. & Jia, J. Exercise preconditioning and brain ischemic tolerance. Neuroscience 177, 170–176 (2011).

    CAS  Article  Google Scholar 

  36. 36

    Dishman, R.K. et al. Neurobiology of exercise. Obesity (Silver Spring) 14, 345–356 (2006).

    CAS  Article  Google Scholar 

  37. 37

    Pedersen, B.K. & Febbraio, M.A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379–1406 (2008).

    CAS  Article  Google Scholar 

  38. 38

    Rasmussen, P. et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp. Physiol. 94, 1062–1069 (2009).

    CAS  Article  Google Scholar 

  39. 39

    Fagan, S., Cronic, L.E. & Hess, D.C. Minocycline development for acute ischemic stroke. Transl. Stroke Res. 2, 202–208 (2011).

    CAS  Article  Google Scholar 

  40. 40

    Bath, P.M. & Sprigg, N. Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke. Cochrane Database of Systematic Reviews CD005207, published online, doi:10.1002/14651858.CD005207.pub3 (2007).

  41. 41

    Ehrenreich, H. et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 40, e647–e656 (2009).

    CAS  Article  Google Scholar 

  42. 42

    Tang, X.N. & Yenari, M.A. Hypothermia as a cytoprotective strategy in ischemic tissue injury. Ageing Res. Rev. 9, 61–68 (2010).

    Article  Google Scholar 

  43. 43

    Hemmen, T.M. et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke 41, 2265–2270 (2010).

    Article  Google Scholar 

  44. 44

    Koch, S., Katsnelson, M., Dong, C. & Perez-Pinzon, M. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke 42, 1387–1391 (2011).

    Article  Google Scholar 

  45. 45

    Ren, C. et al. Limb remote ischemic postconditioning protects against focal ischemia in rats. Brain Res. 1288, 88–94 (2009).

    CAS  Article  Google Scholar 

  46. 46

    Dreixler, J.C. et al. Delayed post-ischemic conditioning significantly improves the outcome after retinal ischemia. Exp. Eye Res. 92, 521–527 (2011).

    CAS  Article  Google Scholar 

  47. 47

    Stapels, M. et al. Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance. Sci. Signal. 3, ra15 (2010).

    Article  Google Scholar 

  48. 48

    Morris, K.C., Lin, H.W., Thompson, J.W. & Perez-Pinzon, M.A. Pathways for ischemic cytoprotection: Role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. J. Cereb. Blood Flow Metab. 31, 1003–1019 (2011).

    CAS  Article  Google Scholar 

  49. 49

    Stenzel-Poore, M.P. et al. Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 362, 1028–1037 (2003).

    CAS  Article  Google Scholar 

  50. 50

    Marsh, B. et al. Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. J. Neurosci. 29, 9839–9849 (2009).

    CAS  Article  Google Scholar 

Download references


This work was supported by US National Institutes of Health grants R37-NS34179 and NS35806.

Author information



Corresponding author

Correspondence to Costantino Iadecola.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1 (PDF 108 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Iadecola, C., Anrather, J. Stroke research at a crossroad: asking the brain for directions. Nat Neurosci 14, 1363–1368 (2011).

Download citation

Further reading