Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

A new penumbra: transitioning from injury into repair after stroke

Nature Medicine volume 14, pages 497–500 (2008)Cite this article

Abstract

The penumbra is an area of brain tissue that is damaged but not yet dead after focal ischemia. The existence of a penumbra implies that therapeutic salvage is theoretically possible after stroke. The first decade of penumbral science investigated the ischemic regulation of electrophysiology, cerebral blood flow and metabolism. The second decade advanced our understanding of molecular mechanisms that mediate penumbral cell death. And the third decade saw the rapid development of clinical neuroimaging tools that are now increasingly applied in stroke patients. But how can we look ahead as we move into the fourth decade of penumbra research? This author speculates that a paradigm shift is needed. Most molecular targets for therapy have biphasic roles in stroke pathophysiology. During the acute phase, these targets mediate injury. During the recovery phase, the same mediators contribute to neurovascular remodeling. It is this boundary zone that comprises the new penumbra, and future investigations should dissect where, when and how damaged brain makes the transition from injury into repair.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The penumbra.

Similar content being viewed by others

References

  1. Astrup, J., Symon, L., Branston, N.M. & Lassen, N.A. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke 8, 51–57 (1977).

    Article  CAS  Google Scholar 

  2. Ginsberg, M.D. Local metabolic responses to cerebral ischemia. Cerebrovasc. Brain Metab. Rev. 2, 58–93 (1990).

    CAS  PubMed  Google Scholar 

  3. Heiss, W.D. Flow thresholds of functional and morphological damage of brain tissue. Stroke 14, 329–331 (1983).

    Article  CAS  Google Scholar 

  4. Powers, W.J., Grubb, R.L. Jr & Raichle, M.E. Physiological responses to focal cerebral ischemia in humans. Ann. Neurol. 16, 546–552 (1984).

    Article  CAS  Google Scholar 

  5. Lo, E.H., Moskowitz, M.A. & Jacobs, T.P. Exciting, radical, suicidal: how brain cells die after stroke. Stroke 36, 189–192 (2005).

    Article  Google Scholar 

  6. Sharp, F.R., Lu, A., Tang, Y. & Millhorn, D.E. Multiple molecular penumbras after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 20, 1011–1032 (2000).

    Article  CAS  Google Scholar 

  7. Baron, J.C. Mapping the ischaemic penumbra with PET: a new approach. Brain 124, 2–4 (2001).

    Article  CAS  Google Scholar 

  8. Heiss, W.D. Ischemic penumbra: evidence from functional imaging in man. J. Cereb. Blood Flow Metab. 20, 1276–1293 (2000).

    Article  CAS  Google Scholar 

  9. Schlaug, G. et al. The ischemic penumbra: operationally defined by diffusion and perfusion MRI. Neurology 53, 1528–1537 (1999).

    Article  CAS  Google Scholar 

  10. Warach, S. Measurement of the ischemic penumbra with MRI: it's about time. Stroke 34, 2533–2534 (2003).

    Article  Google Scholar 

  11. Hoyte, L., Kaur, J. & Buchan, A.M. Lost in translation: taking neuroprotection from animal models to clinical trials. Exp. Neurol. 188, 200–204 (2004).

    Article  CAS  Google Scholar 

  12. Lo, E.H. Experimental models, neurovascular mechanisms and translational issues in stroke research. Br. J. Pharmacol. 153, S396–S405 (2008)

    Article  CAS  Google Scholar 

  13. Lo, E.H., Dalkara, T. & Moskowitz, M.A. Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4, 399–415 (2003).

    Article  CAS  Google Scholar 

  14. Young, D., Lawlor, P.A., Leone, P., Dragunow, M. & During, M.J. Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat. Med. 5, 448–453 (1999).

    Article  CAS  Google Scholar 

  15. Ikonomidou, C., Stefovska, V. & Turski, L. Neuronal death enhanced by N-methyl-D-aspartate antagonists. Proc. Natl. Acad. Sci. USA 97, 12885–12890 (2000).

    Article  CAS  Google Scholar 

  16. Arvidsson, A., Kokaia, Z. & Lindvall, O. N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur. J. Neurosci. 14, 10–18 (2001).

    Article  CAS  Google Scholar 

  17. Papadia, S., Stevenson, P., Hardingham, N.R., Bading, H. & Hardingham, G.E. Nuclear Ca2+ and the cAMP response element–binding protein family mediate a late phase of activity-dependent neuroprotection. J. Neurosci. 25, 4279–4287 (2005).

    Article  CAS  Google Scholar 

  18. Ikonomidou, C. & Turski, L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol. 1, 383–386 (2002).

    Article  CAS  Google Scholar 

  19. Cunningham, L.A., Wetzel, M. & Rosenberg, G.A. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50, 329–339 (2005).

    Article  Google Scholar 

  20. Wang, X. et al. Lipoprotein receptor–mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat. Med. 9, 1313–1317 (2003).

    Article  CAS  Google Scholar 

  21. Wang, X. et al. Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke. Stroke 35, 2726–2730 (2004).

    Article  CAS  Google Scholar 

  22. Zhao, B.Q. et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat. Med. 12, 441–445 (2006).

    Article  CAS  Google Scholar 

  23. Lee, S.R. et al. Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J. Neurosci. 26, 3491–3495 (2006).

    Article  CAS  Google Scholar 

  24. Zhao, B.Q., Tejima, E. & Lo, E.H. Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke 38, 748–752 (2007).

    Article  CAS  Google Scholar 

  25. Gao, Y. et al. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. J. Cereb. Blood Flow Metab. 25, 694–712 (2005).

    Article  CAS  Google Scholar 

  26. Borsello, T. et al. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat. Med. 9, 1180–1186 (2003).

    Article  CAS  Google Scholar 

  27. Waetzig, V., Zhao, Y. & Herdegen, T. The bright side of JNKs—multitalented mediators in neuronal sprouting, brain development and nerve fiber regeneration. Prog. Neurobiol. 80, 84–97 (2006).

    Article  CAS  Google Scholar 

  28. Lees, K.R. et al. NXY-059 for acute ischemic stroke. N. Engl. J. Med. 354, 588–600 (2006).

    Article  CAS  Google Scholar 

  29. Shuaib, A. et al. NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med. 357, 562–571 (2007).

    Article  CAS  Google Scholar 

  30. Ginsberg, M.D. Life after cerovive: a personal perspective on ischemic neuroprotection in the post–NXY-059 era. Stroke 38, 1967–1972 (2007).

    Article  Google Scholar 

  31. Savitz, S.I. & Fisher, M. Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann. Neurol. 61, 396–402 (2007).

    Article  CAS  Google Scholar 

  32. Dirnagl, U., Iadecola, C. & Moskowitz, M.A. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397 (1999).

    Article  CAS  Google Scholar 

  33. Huang, Z. et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265, 1883–1885 (1994).

    Article  CAS  Google Scholar 

  34. Iadecola, C., Pelligrino, D.A., Moskowitz, M.A. & Lassen, N.A. Nitric oxide synthase inhibition and cerebrovascular regulation. J. Cereb. Blood Flow Metab. 14, 175–192 (1994).

    Article  CAS  Google Scholar 

  35. Lo, E.H. et al. Temporal correlation mapping analysis of the hemodynamic penumbra in mutant mice deficient in endothelial nitric oxide synthase gene expression. Stroke 27, 1381–1385 (1996).

    Article  CAS  Google Scholar 

  36. Rhee, S.G. Cell signaling. H2O2, a necessary evil for cell signaling. Science 312, 1882–1883 (2006).

    Article  Google Scholar 

  37. Chen, J. et al. Niaspan increases angiogenesis and improves functional recovery after stroke. Ann. Neurol. 62, 49–58 (2007).

    Article  CAS  Google Scholar 

  38. Ushio-Fukai, M. Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc. Res. 71, 226–235 (2006).

    Article  CAS  Google Scholar 

  39. Shin, H.K. et al. Vasoconstrictive neurovascular coupling during focal ischemic depolarizations. J. Cereb. Blood Flow Metab. 26, 1018–1030 (2006).

    Article  Google Scholar 

  40. Bazan, N.G., Marcheselli, V.L. & Cole-Edwards, K. Brain response to injury and neurodegeneration: endogenous neuroprotective signaling. Ann. NY Acad. Sci. 1053, 137–147 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Stenzel-Poore, M.P., Stevens, S.L., King, J.S. & Simon, R.P. Preconditioning reprograms the response to ischemic injury and primes the emergence of unique endogenous neuroprotective phenotypes: a speculative synthesis. Stroke 38, 680–685 (2007).

    Article  Google Scholar 

  43. Sun, F., Gobbel, G., Li, W. & Chen, J. Molecular mechanisms of DNA damage and repair in ischemic neuronal injury. in Acute Ischemic Injury and Repair in the Nervous System (ed. Chan, P.H.) 65–87 (Springer, New York, 2007).

    Google Scholar 

  44. Wahlgren, N.G. & Ahmed, N. Neuroprotection in cerebral ischaemia: facts and fancies—the need for new approaches. Cerebrovasc. Dis. 17 Suppl 1, 153–166 (2004).

    Article  CAS  Google Scholar 

  45. Furlan, A.J. et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 37, 1227–1231 (2006).

    Article  CAS  Google Scholar 

  46. Hacke, W. et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 36, 66–73 (2005).

    Article  CAS  Google Scholar 

  47. Albers, G.W. et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann. Neurol. 60, 508–517 (2006).

    Article  Google Scholar 

  48. Kidwell, C.S. et al. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann. Neurol. 47, 462–469 (2000).

    Article  CAS  Google Scholar 

  49. Moustafa, R.R. & Baron, J.C. Pathophysiology of ischaemic stroke: insights from imaging, and implications for therapy and drug discovery. Br. J. Pharmacol. 153, S44–S54 (2008).

    Article  CAS  Google Scholar 

  50. Chopp, M., Zhang, Z.G. & Jiang, Q. Neurogenesis, angiogenesis, and MRI indices of functional recovery from stroke. Stroke 38, 827–831 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

The speculative ideas presented here have come from innumerable stimulating discussions with many colleagues over the past few years, especially in the context of the stroke progress review group organized by the National Institute of Neurological Disorders and Stroke. I apologize to colleagues whose work could not be cited because of space limitations. Supported in part by a Bugher award from the American Heart Association and grants from the US National Institutes of Health.

Author information

Authors and Affiliations

  1. Eng H. Lo is at the Neuroprotection Research Laboratory, Massachusetts General Hospital, and the Program in Neuroscience, Harvard Medical School, Massachusetts General Hospital East 149-2401, Charlestown, Massachusetts 02129, USA. Lo@helix.mgh.harvard.edu,

    Eng H Lo

Authors
  1. Eng H Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lo, E. A new penumbra: transitioning from injury into repair after stroke. Nat Med 14, 497–500 (2008). https://doi.org/10.1038/nm1735

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1735

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing