Skip to main content

Advertisement

SpringerLink
Log in

Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke

  • Cell Death and Disease
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

It has been a major challenge to develop effective therapeutics for stroke, a leading cause of death and serious debilitation. Intensive research in the past 15 years have implicated many regulators and the related mechanisms by which neuronal cell death is regulated. It is now clear that even a brief ischemic stroke may trigger complex cellular events that lead to both apoptotic and necrotic neuronal cell death in a progressive manner. Although efforts at developing specific chemical inhibitors for validated targets have been successful for in vitro enzymatic assays, the development of some of such inhibitors into human therapy has been often hindered by their in vivo bioavailability profile. Considerations for the ability to chemically target a cellular mechanism in manner compatible with disease targets in vivo might be emphasized early in the development process by putting a priority on identifying key targets that can be effectively targeted chemically. Thorough interrogation of cellular pathways by saturation chemical genetics may provide a novel strategy to identify multiple key molecular entities that can be targeted chemically in order to select a target suitable for the treatment of intended human diseases such as stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Reference

  1. Li J, Yuan J (2008) Caspases in apoptosis and beyond. Oncogene 27:6194–6206. doi:10.1038/onc.2008.297

    Article  PubMed  CAS  Google Scholar 

  2. Cao G, Pei W, Ge H et al (2002) In Vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J Neurosci 22:5423–5431

    PubMed  CAS  Google Scholar 

  3. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219. doi:10.1016/S0092-8674(04)00046-7

    Article  PubMed  CAS  Google Scholar 

  4. Plesnila N, Zinkel S, Amin-Hanjani S, Qiu J, Korsmeyer SJ, Moskowitz MA (2002) Function of BID—a molecule of the bcl-2 family—in ischemic cell death in the brain. Eur Surg Res 34:37–41. doi:10.1159/000048885

    Article  PubMed  CAS  Google Scholar 

  5. Plesnila N, Zinkel S, Le DA et al (2001) BID mediates neuronal cell death after oxygen/glucose deprivation and focal cerebral ischemia. Proc Natl Acad Sci USA 98:15318–15323. doi:10.1073/pnas.261323298

    Article  PubMed  CAS  Google Scholar 

  6. Becattini B, Sareth S, Zhai D et al (2004) Targeting apoptosis via chemical design: inhibition of bid-induced cell death by small organic molecules. Chem Biol 11:1107–1117. doi:10.1016/j.chembiol.2004.05.022

    Article  PubMed  CAS  Google Scholar 

  7. Hara H, Friedlander RM, Gagliardini V et al (1997) Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 94:2007–2012. doi:10.1073/pnas.94.5.2007

    Article  PubMed  CAS  Google Scholar 

  8. Hara H, Fink K, Endres M et al (1997) Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein. J Cereb Blood Flow Metab 17:370–375. doi:10.1097/00004647-199704000-00002

    Article  PubMed  CAS  Google Scholar 

  9. Schielke GP, Yang GY, Shivers BD, Betz AL (1998) Reduced ischemic brain injury in interleukin-1 beta converting enzyme-deficient mice. J Cereb Blood Flow Metab 18:180–185. doi:10.1097/00004647-199802000-00009

    Article  PubMed  CAS  Google Scholar 

  10. Le DA, Wu Y, Huang Z et al (2002) Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci USA 99:15188–15193. doi:10.1073/pnas.232473399

    Article  PubMed  CAS  Google Scholar 

  11. Hayashi Y, Jikihara I, Yagi T et al (2001) Immunohistochemical investigation of caspase-1 and effect of caspase-1 inhibitor in delayed neuronal death after transient cerebral ischemia. Brain Res 893:113–120. doi:10.1016/S0006-8993(00)03307-2

    Article  PubMed  CAS  Google Scholar 

  12. Relton JK, Rothwell NJ (1992) Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res Bull 29:243–246. doi:10.1016/0361-9230(92)90033-T

    Article  PubMed  CAS  Google Scholar 

  13. Betz AL, Yang GY, Davidson BL (1995) Attenuation of stroke size in rats using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist in brain. J Cereb Blood Flow Metab 15:547–551

    PubMed  CAS  Google Scholar 

  14. Lawrence CB, Allan SM, Rothwell NJ (1998) Interleukin-1beta and the interleukin-1 receptor antagonist act in the striatum to modify excitotoxic brain damage in the rat. Eur J NeuroSci 10:1188–1195. doi:10.1046/j.1460-9568.1998.00136.x

    Article  PubMed  CAS  Google Scholar 

  15. Tehranian R, Andell-Jonsson S, Beni SM et al (2002) Improved recovery and delayed cytokine induction after closed head injury in mice with central overexpression of the secreted isoform of the interleukin-1 receptor antagonist. J Neurotrauma 19:939–951. doi:10.1089/089771502320317096

    Article  PubMed  Google Scholar 

  16. Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ (2001) Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci 21:5528–5534

    PubMed  CAS  Google Scholar 

  17. Emsley HC, Smith CJ, Georgiou RF et al (2005) A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 76:1366–1372. doi:10.1136/jnnp.2004.054882

    Article  PubMed  CAS  Google Scholar 

  18. Barres BA (2008) The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60:430–440. doi:10.1016/j.neuron.2008.10.013

    Article  PubMed  CAS  Google Scholar 

  19. Friedlander RM, Gagliardini V, Rotello RJ, Yuan J (1996) Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta-converting enzyme-mediated apoptosis. J Exp Med 184:717–724. doi:10.1084/jem.184.2.717

    Article  PubMed  CAS  Google Scholar 

  20. Keller M, Ruegg A, Werner S, Beer HD (2008) Active caspase-1 is a regulator of unconventional protein secretion. Cell 132:818–831. doi:10.1016/j.cell.2007.12.040

    Article  PubMed  CAS  Google Scholar 

  21. Benchoua A, Guegan C, Couriaud C et al (2001) Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci 21:7127–7134

    PubMed  CAS  Google Scholar 

  22. Li H, Colbourne F, Sun P, Zhao Z, Buchan AM, Iadecola C (2000) Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 31:176–182

    PubMed  CAS  Google Scholar 

  23. Manabat C, Han BH, Wendland M et al (2003) Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after stroke in immature brain. Stroke 34:207–213. doi:10.1161/01.STR.0000047101.87575.3C

    Article  PubMed  CAS  Google Scholar 

  24. Irving EA, Bamford M (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631–647. doi:10.1097/00004647-200206000-00001

    Article  PubMed  CAS  Google Scholar 

  25. Borsello T, Clarke PG, Hirt L et al (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9:1180–1186. doi:10.1038/nm911

    Article  PubMed  CAS  Google Scholar 

  26. Bennett BL, Sasaki DT, Murray BW et al (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 98:13681–13686. doi:10.1073/pnas.251194298

    Article  PubMed  CAS  Google Scholar 

  27. Gao Y, Signore AP, Yin W et al (2005) 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. doi:10.1038/sj.jcbfm.9600062

    Article  PubMed  CAS  Google Scholar 

  28. Guan QH, Pei DS, Liu XM, Wang XT, Xu TL, Zhang GY (2006) Neuroprotection against ischemic brain injury by SP600125 via suppressing the extrinsic and intrinsic pathways of apoptosis. Brain Res 1092:36–46. doi:10.1016/j.brainres.2006.03.086

    Article  PubMed  CAS  Google Scholar 

  29. Kuan CY, Whitmarsh AJ, Yang DD et al (2003) A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci USA 100:15184–15189. doi:10.1073/pnas.2336254100

    Article  PubMed  CAS  Google Scholar 

  30. Okuno S, Saito A, Hayashi T, Chan PH (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24:7879–7887. doi:10.1523/JNEUROSCI.1745-04.2004

    Article  PubMed  CAS  Google Scholar 

  31. Putcha GV, Le S, Frank S et al (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38:899–914. doi:10.1016/S0896-6273(03)00355-6

    Article  PubMed  CAS  Google Scholar 

  32. Herdegen T, Claret FX, Kallunki T et al (1998) Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 18:5124–5135

    PubMed  CAS  Google Scholar 

  33. Wei L, Ying DJ, Cui L, Langsdorf J, Yu SP (2004) Necrosis, apoptosis and hybrid death in the cortex and thalamus after barrel cortex ischemia in rats. Brain Res 1022:54–61. doi:10.1016/j.brainres.2004.06.080

    Article  PubMed  CAS  Google Scholar 

  34. Unal-Cevik I, Kilinc M, Can A, Gursoy-Ozdemir Y, Dalkara T (2004) Apoptotic and necrotic death mechanisms are concomitantly activated in the same cell after cerebral ischemia. Stroke 35:2189–2194. doi:10.1161/01.STR.0000136149.81831.c5

    Article  PubMed  Google Scholar 

  35. Liu CL, Siesjo BK, Hu BR (2004) Pathogenesis of hippocampal neuronal death after hypoxia-ischemia changes during brain development. Neuroscience 127:113–123. doi:10.1016/j.neuroscience.2004.03.062

    Article  PubMed  CAS  Google Scholar 

  36. Zhang J, Dawson VL, Dawson TM, Snyder SH (1994) Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science 263:687–689. doi:10.1126/science.8080500

    Article  PubMed  CAS  Google Scholar 

  37. Beckman JS (1991) The double-edged role of nitric oxide in brain function and superoxide-mediated injury. J Dev Physiol 15:53–59

    PubMed  CAS  Google Scholar 

  38. Amé JC, Jacobson EL, Jacobson MK (2000) ADP-ribose polymer metabolism. Oxford University Press, New York

    Google Scholar 

  39. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC (1994) Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371:346–347. doi:10.1038/371346a0

    Article  PubMed  CAS  Google Scholar 

  40. Yap E, Tan WL, Ng I, Ng YK (2008) Combinatorial-approached neuroprotection using pan-caspase inhibitor and poly (ADP-ribose) polymerase (PARP) inhibitor following experimental stroke in rats; is there additional benefit? Brain Res 1195:130–138. doi:10.1016/j.brainres.2007.12.024

    Article  PubMed  CAS  Google Scholar 

  41. Yu SW, Wang H, Poitras MF et al (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259–263. doi:10.1126/science.1072221

    Article  PubMed  CAS  Google Scholar 

  42. Eliasson MJ, Sampei K, Mandir AS et al (1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3:1089–1095. doi:10.1038/nm1097-1089

    Article  PubMed  CAS  Google Scholar 

  43. Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA (1997) Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab 17:1143–1151. doi:10.1097/00004647-199711000-00002

    Article  PubMed  CAS  Google Scholar 

  44. McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD (2005) Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 25:502–512. doi:10.1038/sj.jcbfm.9600059

    Article  PubMed  CAS  Google Scholar 

  45. Krishnakumar R, Gamble MJ, Frizzell KM, Berrocal JG, Kininis M, Kraus WL (2008) Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science 319:819–821. doi:10.1126/science.1149250

    Article  PubMed  CAS  Google Scholar 

  46. Ju BG, Lunyak VV, Perissi V et al (2006) A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science 312:1798–1802. doi:10.1126/science.1127196

    Article  PubMed  CAS  Google Scholar 

  47. Xu K, Tavernarakis N, Driscoll M (2001) Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca(2+) release from the endoplasmic reticulum. Neuron 31:957–971. doi:10.1016/S0896-6273(01)00432-9

    Article  PubMed  CAS  Google Scholar 

  48. Yamashima T, Saido TC, Takita M et al (1996) Transient brain ischaemia provokes Ca2+, PIP2 and calpain responses prior to delayed neuronal death in monkeys. Eur J NeuroSci 8:1932–1944. doi:10.1111/j.1460-9568.1996.tb01337.x

    Article  PubMed  CAS  Google Scholar 

  49. Yamashima T (2004) Ca2+-dependent proteases in ischemic neuronal death: a conserved ‘calpain-cathepsin cascade’ from nematodes to primates. Cell Calcium 36:285–293. doi:10.1016/j.ceca.2004.03.001

    Article  PubMed  CAS  Google Scholar 

  50. Hong SC, Goto Y, Lanzino G, Soleau S, Kassell NF, Lee KS (1994) Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke 25:663–669

    PubMed  CAS  Google Scholar 

  51. Degterev A, Huang Z, Boyce M et al (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119. doi:10.1038/nchembio711

    Article  PubMed  CAS  Google Scholar 

  52. Degterev A, Hitomi J, Germscheid M et al (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4:313–321. doi:10.1038/nchembio.83

    Article  PubMed  CAS  Google Scholar 

  53. Holler N, Zaru R, Micheau O et al (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1:489–495. doi:10.1038/82732

    Article  PubMed  CAS  Google Scholar 

  54. Martin-Villalba A, Hahne M, Kleber S et al (2001) Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke. Cell Death Differ 8:679–686. doi:10.1038/sj.cdd.4400882

    Article  PubMed  CAS  Google Scholar 

  55. Teng X, Degterev A, Jagtap P et al (2005) Structure-activity relationship study of novel necroptosis inhibitors. Bioorg Med Chem Lett 15:5039–5044. doi:10.1016/j.bmcl.2005.07.077

    Article  PubMed  CAS  Google Scholar 

  56. Wang K, Li J, Degterev A, Hsu E, Yuan J, Yuan C (2007) Structure-activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5. Bioorg Med Chem Lett 17:1455–1465. doi:10.1016/j.bmcl.2006.11.056

    Article  PubMed  CAS  Google Scholar 

  57. You Z, Savitz S, Yang J, Degterev A, Yuan J, Cuny GD, Moskowitz MA, Whalen MJ (2008) Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab 28:1564–1573

    Article  PubMed  CAS  Google Scholar 

  58. Lim SY, Davidson SM, Mocanu MM, Yellon DM, Smith CC (2007) The cardioprotective effect of necrostatin requires the cyclophilin-D component of the mitochondrial permeability transition pore. Cardiovasc Drugs Ther 21:467–469. doi:10.1007/s10557-007-6067-6

    Article  PubMed  CAS  Google Scholar 

  59. Hitomi J, Christofferson DE, Ng A, et al (2008) Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135:1311–1323

    Article  PubMed  CAS  Google Scholar 

  60. Schreiber SL (1998) Chemical genetics resulting from a passion for synthetic organic chemistry. Bioorg Med Chem 6:1127–1152. doi:10.1016/S0968-0896(98)00126-6

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The author expresses deep gratitude to Dr. Mike Moskowitz for insightful comments and suggestions. This work was supported in part by a NIH Director’s Pioneer Award (DP1OD000580), grants from the National Institute of Neurological Disorders and Stroke (UO1 NS050560) and the National Institute on Aging (R37-AG012859 and PO1 AG027916).

Author information

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA, 02115, USA

    Junying Yuan

Authors
  1. Junying Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junying Yuan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuan, J. Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis 14, 469–477 (2009). https://doi.org/10.1007/s10495-008-0304-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-008-0304-8

Keywords

Search

Navigation