Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke

  • Bruce Ovbiagele
  • Chelsea S. Kidwell
  • Sidney Starkman
  • Jeffrey L. Saver

Opinion statement

Currently, intravenous recombinant tissue plasminogen activator is the only US Food and Drug Administration-approved therapy for acute ischemic stroke. Although efficacious, its usefulness is limited, mainly because of the very limited time window for its administration. Neuroprotective treatments are therapies that block the cellular, biochemical, and metabolic elaboration of injury during or after exposure to ischemia, and have a potential role in ameliorating brain injury in patients with acute ischemic stroke. More than 50 neuroprotective agents have reached randomized human clinical trials in focal ischemic stroke, but none have been unequivocally proven efficacious, despite successful preceding animal studies. The failed neuroprotective trials of the past have greatly increased understanding of the fundamental biology of ischemic brain injury and have laid a strong foundation for future advance. Moreover, the recent favorable results of human clinical trials of hypothermia in human cardiac arrest and global brain ischemia have validated the general concept of neuroprotection for ischemic brain injury. Recent innovations in strategies of preclinical drug development and clinical trial design that rectify past defects hold great promise for neuroprotective investigation, including novel approaches to accelerating time to initiation of experimental treatment, use of outcome measures sensitive to treatment effects, and trial testing of combination therapies rather than single agents alone. Although no neuroprotective agent is of proven benefit for focal ischemic stroke, several currently available interventions have shown promising results in preliminary trials and may be considered for cautious, off-label use in acute stroke, including hypothermia, magnesium sulfate, citicoline, albumin, and erythropoietin. Overall, the prospects for safe and effective neuroprotective therapies to improve stroke outcome remain promising.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Tissue plasminogen activator for acute ischemic stroke: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995, 333:1581–1587.Google Scholar
  2. 2.
    Nilasena D, Kresowik TF, Wiblin RT, et al.: Assessing patterns of t-PA use in acute stroke. Stroke 2002, 33:354.Google Scholar
  3. 3.
    Fisher M, Ratan R: New perspectives on developing acute stroke therapy. Ann Neurol 2003, 53:10–20.PubMedCrossRefGoogle Scholar
  4. 4.
    Ovbiagele B, Kidwell CS, Starkman S, Saver JL: Neuroprotective agents for the treatment of acute ischemic stroke. Curr Neurol Neurosci Rep 2003, 3:9–20.PubMedCrossRefGoogle Scholar
  5. 5.
    Lutsep HL, Clark WM: Neuroprotection in acute ischaemic stroke: current status and future potential. Drugs R D 1999, 1:3–8.PubMedGoogle Scholar
  6. 6.
    Kidwell CS: Trends in acute ischemic stroke trials through the 20th century. Stroke 2001, 32:1349–1359.PubMedGoogle Scholar
  7. 7.
    DeGraba TJ, Pettigrew LC: Why do neuroprotective drugs work in animals but not humans? Neurol Clin 2000, 18:475–493.PubMedCrossRefGoogle Scholar
  8. 8.
    Grotta J: Why do all drugs work in animals but none in stroke patients? 2. Neuroprotective therapy. J Intern Med 1995, 237:89–94.PubMedCrossRefGoogle Scholar
  9. 9.
    Felberg RBW, Grotta JC: Neuroprotection and the ischemic cascade. CNS Spectr 2000, 5:52–58.PubMedGoogle Scholar
  10. 10.
    Clark W: Reperfusion injury in stroke. Emedicine Journal 2001, 2:12. http://www.emedicine.com.Google Scholar
  11. 11.
    Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999, 30:2752–2758. First joint recommendations of this academic and industry panel of experts, offering guidelines for preclinical assessments of potential neuroprotective therapies for the treatment of acute stroke.Google Scholar
  12. 12.
    STAIR Roundtable: Recommendations for clinical trial evaluation of acute stroke therapies. Stroke 2001, 32:1598–1606. Second meeting of the STAIR ad hoc expert panelists providing guidelines for the design of pilot and pivotal human clinical trials of neuroprotective and other therapies for acute ischemic stroke.Google Scholar
  13. 13.
    Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. The Hypothermia after Cardiac Arrest Study Group [no authors listed]. N Engl J Med 2002, 34:549–556. A landmark multicenter trial that revealed that therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality in patients who have been successfully resuscitated after cardiac arrest caused by ventricular fibrillation, thus buttressing the neuroprotective principle.Google Scholar
  14. 14.
    Schwab SSS, Spranger M, Keller E, et al.: Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998, 29:2461–2466.PubMedGoogle Scholar
  15. 15.
    Kasner SE: Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial. Stroke 2002, 33:130–134.PubMedCrossRefGoogle Scholar
  16. 16.
    Kammersgaard LRB, Jorgensen HS, Reith J, et al.: Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: a case-control study. The Copenhagen Stroke Study. Stroke 2000, 31:2251–2256.PubMedGoogle Scholar
  17. 17.
    Georgiadis DSS, Kollmar R, Schwab S: Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach. Stroke 2001, 32:2550–2553.PubMedGoogle Scholar
  18. 18.
    Krieger DW: Cooling acute ischemic brain damage: a randomized pilot trial of endovascular cooling for patients with acute ischemic stroke. Stroke 2003, 34:248A.Google Scholar
  19. 19.
    Lyden P: Phase I study of endovascular-induced hypothermia in patients with acute ischemic stroke. Stroke 2003, 34:249A.CrossRefGoogle Scholar
  20. 20.
    Muir KW: Magnesium for neuroprotection in ischaemic stroke: rationale for use and evidence of effectiveness. CNS Drugs 2001, 15:921–930.PubMedCrossRefGoogle Scholar
  21. 21.
    Ferguson KKC, Starkman S, Saver JL: Hyperacute treatment initiation in neuroprotective stroke trials. Neurology 2002, 58(suppl):A387.Google Scholar
  22. 22.
    Saver JKC, Leary MC, Ovbiagele B, et al.: Results of the Field Administration of Stroke Treatment-Magnesium (FAST-MAG) pilot trial: a study of pre-hospital neuroprotective therapy. Stroke 2002, 33:353. First of its kind study of prehospital application of neuroprotective therapy for acute ischemic stroke, demonstrating feasibility and significant acceleration of treatment start when compared with in-hospital initiation of neuroprotective therapy.Google Scholar
  23. 23.
    Kollmar R: Neuroprotective effect of delayed moderate hypothermia after focal cerebral ischemia: an MRI study. Stroke 2002, 33:1899–1904.PubMedCrossRefGoogle Scholar
  24. 24.
    Kammersgaard LP: Admission body temperature predicts long-term mortality after acute stroke: the Copenhagen Stroke Study. Stroke 2002, 33:1759–1762.PubMedCrossRefGoogle Scholar
  25. 25.
    Bernard SGT, Buist MD, Jones BM, et al.: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002, 346:557–563.PubMedCrossRefGoogle Scholar
  26. 26.
    Bradford A, Lees K: Design of the intravenous magnesium efficacy in acute stroke trial (IMAGES). Curr Control Trials Cardiovasc Med 2000, 1:184–190.PubMedCrossRefGoogle Scholar
  27. 27.
    Saver JWJ: Choline precursors in acute and subacute human stroke: a meta-analysis. Stroke 2002, 33:353.Google Scholar
  28. 28.
    Warach SHK: Dose dependent reduction in infarct growth with citicholine treatment: evidence of neuroprotection in human stroke? Stroke 2002, 33:354.Google Scholar
  29. 29.
    Belayev L: Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke 2002, 33:1077–1084.PubMedCrossRefGoogle Scholar
  30. 30.
    Belayev L: Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke 2001, 32:553–560.PubMedGoogle Scholar
  31. 31.
    Ginsberg MD: Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis lecture. Stroke 2003, 34:214–223.PubMedCrossRefGoogle Scholar
  32. 32.
    Brines M: What evidence supports use of erythropoietin as a novel neurotherapeutic? Oncology 2002, 16(suppl):79–89.PubMedGoogle Scholar
  33. 33.
    Ehrenreich HHM, Piotr L, Dembowski C, et al.: Erythropoietin treatment for acute stroke: a randomized double blind proof of concept trial in man. Stroke 2002, 33:354.Google Scholar
  34. 34.
    Grotta JSR, Aronowski JA: Tx ethanol plus caffeine (caffeinol) neuroprotection for ischemic stroke: further studies in preparation for human trials. Stroke 2002, 33:402.Google Scholar
  35. 35.
    Lyden P: The Clomethiazole Acute Stroke Study in tissuetype plasminogen activator-treated stroke (CLASS-T): final results. Neurology 2001, 57:1199–1205. This study is an example of the first generation of combination tissue-type plasminogen activator plus add-on neuroprotective agent trials. Demonstrated the feasibility and safety of adding the neuroprotectant clomethiazole to under 3-hour fibrinolytic therapy in patients with acute ischemic stroke.PubMedGoogle Scholar
  36. 36.
    Grotta J: Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc Dis 2001, 12:258–263.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • Bruce Ovbiagele
    • 1
  • Chelsea S. Kidwell
  • Sidney Starkman
  • Jeffrey L. Saver
  1. 1.Stroke Center and Department of NeurologyUniversity of California at Los AngelesLos AngelesUSA

Personalised recommendations