Skip to main content Accessibility help
×
Home
  • Cited by 1
  • Print publication year: 2020
  • Online publication date: December 2020

Chapter 12 - Neuroprotection for Acute Brain Ischaemia

from Part III - Acute Treatment of Ischaemic Stroke and Transient Ischaemic Attack

Summary

More than 20,000 patients have participated in clinical trials of more than 100 neuroprotective therapies, but no study has provided convincing evidence of benefit. Several improvements to the rigor of preclinical agent qualification have been identified to increase the likelihood of success in human clinical trials: stringent randomization and blinding techniques to mitigate observer bias; assessment in in time periods achievable in the clinical setting; testing in older animals with comorbidities; and robust and reproducible benefit magnitudes. Human clinical trials should start agents hyperacutely, in the first minutes and hours after onset, when treatment effect would be maximal; target enrolment of patients likely to have transient rather than permanent ischaemic exposure; and use factorial and platform trial designs that would permit efficient testing of combinations of agents able to block multiple ischaemic injury-mediating pathways concurrently, including both anti-necrotic and anti-apoptotic interventions. For agents that allow cells to endure ischaemic stress, human trial delivery approaches include: prehospital initiation; initiation immediately upon brain imaging in patients destined for endovascular intervention; and initiation at outside hospitals in patients undergoing transfer to a neurothrombectomy center. For agents that mitigate reperfusion injury, treatment start before or concurrent with reperfusion, including intra-arterial administration via catheter immediately after endovascular thrombectomy, should be pursued.

Related content

Powered by UNSILO
Aerden, LA, Kessels, FA, Rutten, BP, Lodder, J, Steinbusch, HW. (2004). Diazepam reduces brain lesion size in a photothrombotic model of focal ischemia in rats. Neurosci Lett, 367(1), 76–8.
Arrich, J, Holzer, M, Havel, C, Müllner, M, Herkner, H. (2016). Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev, 2. CD004128. doi:10.1002/14651858.CD004128.pub4.
Bardutzky, J, Shen, Q, Henninger, N, Bouley, J, Duong, TQ, Fisher, M. (2005). Perfusion and diffusion imaging in acute focal cerebral ischemia: temporal vs. spatial resolution. Brain Res, 1043, 155–62.
Bath, PM, Iddenden, R, Bath, FJ, Orgogozo, JM; Tirilazad International Steering Committee. (2001). Tirilazad for acute ischaemic stroke. Cochrane Database Syst Rev, 4. CD002087.
Bath, PMW, Krishnan, K, Appleton, JP. (2017). Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke. Cochrane Database Syst Rev, 4. CD000398. doi:10.1002/14651858.CD000398.pub2.
Bath, PM, Woodhouse, L, Krishnan, K, Anderson, C, Berge, E, Ford, GA, et al. (2016). Effect of treatment delay, stroke type, and thrombolysis on the effect of glyceryl trinitrate, a nitric oxide donor, on outcome after acute stroke: a systematic review and meta-analysis of individual patients from randomised trials. Stroke Res Treat, 9706720. doi:10.1155/2016/9706720.
Belayev, L, Liu, Y, Zhao, W, Busto, R, Ginsberg, MD. (2001). Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke, 32, 553–60.
Bennett, MH, Weibel, S, Wasiak, J, Schnabel, A, French, C, Kranke, P. (2014). Hyperbaric oxygen therapy for acute ischaemic stroke. Cochrane Database Syst Rev, 11. CD004954. doi:10.1002/14651858.CD004954.pub3.
Blanco, M, Nombela, F, Castellanos, M, Rodriguez-Yanez, M, Garcia-Gil, M, Leira, R, et al. (2007). Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology, 69, 904–10.
Candelise, L, Ciccone, A. (2001). Gangliosides for acute ischaemic stroke. Cochrane Database Syst Rev, 4. CD000094.
Chamorro, A, Amaro, S, Castellanos, M, Segura, T, Arenillas, J, Marti-Fabregas, J, et al. (2014). Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol, 13(5), 453–60.
Chandra, B. (1995). A new form of management of stroke. J Stroke Cerebrovasc Dis, 5, 241–3.
Dávalos, A, Alvarez-Sabin, J, Castillo, J, Diez-Teiedor, E, Ferro, J, Martinez-Vila, E, et al. (2012). Citicoline in the treatment of acute ischaemic stroke: an international, randomized, multicenter, placebo-controlled study (ICTUS) trial. Lancet, 380(9839), 349–57.
Davis, SM, Pennypacker, KR. (2017). Targeting antioxidant enzyme expression as a therapeutic strategy for ischemic stroke. Neurochem Int, 107, 2332.
Dhar, R, Misra, H, Diringer, MN. (2017). SANGUINATE™ (pegylated carboxyhemoglobin bovine) improves cerebral blood flow to vulnerable brain regions at risk of delayed cerebral ischemia after subarachnoid hemorrhage. Neurocrit Care, 27, 341–9.
Diener, HC, Lees, KR, Lyden, P, Grotta, J, Davalos, A, Davis, SM, et al. (2008). NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II trials. Stroke, 39, 1751–58.
Doyle, KP, Simon, RP, Stenzel-Poore, MP. (2008). Mechanisms of ischemic brain damage. Neuropharmacology, 55, 310–18.
Emberson, J, Lees, KR, Lyden, P, Blackwell, L, Albers, G, Bluhmki, E, et al.; Stroke Thrombolysis Trialists’ Collaborative Group. (2014). Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet, 384, 1929–35.
England, TJ, Hedstrom, A, O’Sullivan, S, Donnelly, R, Barrett, DA, Sarmad, S, et al. (2017). RECAST (Remote Ischemic Conditioning After Stroke Trial): a pilot randomized placebo controlled phase II trial in acute ischemic stroke. Stroke, 48 , 14121415.
Enlimomab Acute Stroke Trial Investigators. (2001). Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology, 57, 1428–34.
Fagan, SC, Waller, JL, Nichols, FT, Edwards, DJ, Pettigrew, LC, Clark, WM, et al. (2010). Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke, 41(10), 2283–7.
Fisher, M, Feuerstein, G, Howells, DW, Hurn, PD, Kent, TA, Savitz, SI, et al; STAIR Group. (2009). Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke, 40, 2244–50.
Garry, PS, Ezra, M, Rowland, MJ, Westbrook, J, Pattinson, KT. (2015). The role of the nitric oxide pathway in brain injury and its treatment – from bench to bedside. Exp Neurol, 263, 235–43.
Hess, DC, Blauenfeldt, RA, Andersen, G, Hougaard, KD, Hoda, MN, Ding, Y, Ji, X. (2015). Remote ischaemic conditioning – a new paradigm of self-protection in the brain. Nat Rev Neurol, 11, 698710.
Heiss, WD. (2011). The ischemic penumbra: correlates in imaging and implications for treatment of ischemic stroke. Cerebrovasc Dis, 32, 307–20.
Heiss, WD, Thiel, A, Grond, M, Graf, R. (1999). Which targets are relevant for therapy of acute ischemic stroke? Stroke, 30, 1486–9.
Hill, M, Martin, RH, Mikulis, D, Wong, JH, Silver, FL, Terbrugge, KG, et al. (2012). Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol, 11, 942–50.
Hong, K-S, Lee, M, Lee, SH, Hao, Q, Liebeskind, D, Saver, JL. (2011). Acute stroke trials in the 1st decade of the 21st century. Stroke, 42, e314.
Horn, J, De Haan, RJ, Vermeulen, M, Limburg, M. (2001). Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke, 32, 461–5.
Hougaard, KD, Hjort, N, Zeidler, D, Sorensen, L, Norgaard, A, Hansen, TM, et al. (2014). Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke. Stroke, 45, 159167.
Intravenous Magnesium Efficacy in Stroke (IMAGES) Study Investigators. (2004). Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet, 363, 439–45.
Kennedy, J, Hill, MD, Ryckborst, KJ, Eliasziw, M, Demchuk, AM, Buchan, AM; FASTER Investigators. (2007). Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol, 6, 961–69.
Kohler, E, Prentice, DA, Bates, TR, Hankey, GJ, Claxton, A, van Heerden, J, et al. (2013). Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stoke, 44, 2493–9.
Krams, M, Lees, KR, Hacke, W, Grieve, AP, Orgogozo, JM, Ford, GA; ASTIN Study Investigators. (2003). Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke, 34, 2543–8.
Kurisu, K, Yenari, MA. (2018). Therapeutic hypothermia for ischemic stroke; pathophysiology and future promise. Neuropharmacology, 134(Pt B), 302-9. pii: S0028-3908(17)30392–1. doi:10.1016/j.neuropharm.2017.08.025.
Lapchak, PA, Zhang, JH, Noble-Haeusslein, LJ. (2013). RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res, 4, 279–85.
Liu, J, Wang, L-N. (2014). Gamma aminobutyric acid (GABA) receptor agonists for acute stroke. Cochrane Database Syst Rev, 8. CD009622. doi:10.1002/14651858.CD009622.pub3.
Lyden, P, Hemmen, T, Grotta, J, Rapp, K, Ernstrom, K, Rzesiewicz, T, et al. (2016). Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke, 47, 2888–95.
Lyden, P, Shuaib, A, Ng, K, Levin, K, Atkinson, RP, Rajput, A, et al.; CLASS-I/H/T Investigators. (2002). Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results. Stroke, 33(1), 122–8.
Marehbian, J, Greer, DM. (2017). Normothermia and stroke. Curr Treat Options Neurol, 19, 4. doi:10.1007/s11940-017-0437-6.
Martin, RH, Yeatts, SD, Hill, MD, Moy, CS, Ginsberg, MD, Palesch, YY, ALIAS Parts 1 and 2 and NETT investigators. (2016). ALIAS (Albumin in Acute Ischemic Stroke) trials: analysis of the combined data from parts 1 and 2. Stroke, 47, 2355–9.
Montaner, J, Bustamante, J, García-Matas, S, Martinez-Zabaleta, M, Jimenez, C, de la Torre, J, et al. (2016). Combination of thrombolysis and statins in acute stroke is safe: results of the STARS Randomized Trial. Stroke, 47, 2870–3.
Muir, KW, Lees, KR. (2003). Excitatory amino acid antagonists for acute stroke. Cochrane Database Syst Rev, 3, CD001244.
Muscari, A, Puddu, GM, Santoro, N, Serafini, C, Cenni, A, Rossi, V, et al. (2011). The Atorvastatin During Ischemic Stroke Study: a pilot randomized controlled trial . Clin Neuropharm, 34, 141–7.
Narayanan, S, Dave, K, Perez-Pinzon, M. (2013). Ischemic preconditioning and clinical scenarios. Curr Opin Neurol, 26, 17.
O’Collins, VE, Macleod, MR, Donnan, GA, Horky, LL, van der Worp, BH, Howells, DW. (2006). 1,026 experimental treatments in acute stroke. Ann Neurol, 59, 467–77.
Ovbiagele, B, Kidwell, CS, Starkman, S, Saver, JL. (2003). Potential role of neuroprotective agents in the treatment of patients with acute ischemic stroke. Curr Treat Options Neurol, 5, 367–75.
Paciaroni, M, Bogousslavsky, J. (2011). Trafermin for stroke recovery: is it time for another randomized clinical trial? Expert Opin Biol Ther, 11, 1533–41.
Ricci, S, Celani, MG, Cantisani, TA, Righetti, E. (2012). Piracetam for acute ischaemic stroke. Cochrane Database Syst Rev, 9. CD000419. doi:10.1002/14651858.CD000419.pub3.
Romanos, E, Planas, AM, Amaro, S, Chamorro, A. (2007). Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke . J Cereb Blood Flow Metab, 27, 1420.
Saxena, R, Wijnhoud, AD, Carton, H, Hacke, W, Kaste, M, Przybelski, RJ, et al. (1999). Controlled safety study of a hemoglobin-based oxygen carrier, DCLHb, in acute ischemic stroke. Stroke, 30, 993–6.
Saver, JL. (2008). Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair. Rev Neurol Dis, 5, 167–77.
Saver, JL Goyal, M, van der Lugt, A, Menon, BK, Majoie, CB, Dippel, DW, et al. (2016). Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. JAMA, 316, 1279–88.
Saver, JL, Starkman, S., Eckstein, M, Stratton, SJ, Pratt, FD, Hamilton, S, et al. (2015). Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med, 372, 528–36.
Secades, JJ, Alvarez-Sabín, J, Castillo, J, Diez-Tejedor, E, Martinez-Vila, E, Rios, J, et al. (2016). Citicoline for acute ischemic stroke: a systematic review and formal meta-analysis of randomized, double-blind, and placebo-controlled trials. J Stroke Cerebrovasc Dis, 25,1984–96.
Sekerdag, E, Solaroglu, I, Gursoy-Ozdemir, Y. (2018). Cell death mechanisms in stroke and novel molecular and cellular treatment options. Curr Neuropharmacol, 16(9), 13961415. doi:10.2174/1570159X16666180321100439.
Wan, YH, Nie, C, Wang, HL, Huang, CY. (2014). Therapeutic hypothermia (different depths, durations, and rewarming speeds) for acute ischemic stroke: a meta-analysis. J Stroke Cerebrovasc Dis, 23, 2736–47
Wang, Y, Reis, C, Applegate, R 2nd, Stier, G, Martin, R, Zhang, JH. (2015). Ischemic conditioning-induced endogenous brain protection: applications pre-, per- or post-stroke. Exper Neurol, 272, 2640.
Wang, Y, Yoshimura, R, Manabe, H, Schretter, C, Clarke, R, Cai, Y, et al. (2014). Trans-sodium crocetinate improves outcomes in rodent models of occlusive and hemorrhagic stroke. Brain Res, 1583, 245–54.
Wang, Z, Lin, Y, Liu, Y, Chen, Y, Wang, B, Li, C, et al. (2016). Serum uric acid levels and outcomes after acute ischemic stroke. Mol Neurobiol, 53, 1753–9.
Willmot, M, Ghadami, A, Whysall, B, Clarke, W, Wardlaw, J, Bath, PM. (2006). Transdermal glyceryl trinitrate lowers blood pressure and maintains cerebral blood flow in recent stroke. Hypertension, 47, 1209–15.
Yaghi, S, Elkind, MSV. (2016). Lipid control and beyond: current and future indications for statin therapy in stroke. Curr Treat Options Cardio Med, 18, 27. doi:10.1007/s11936-016–0448-8.
Yang, J, Cui, C, Li, J, Zhang, C, Zhang, J, Liu, M. (2015). Edaravone for acute stroke: Meta-analyses of data from randomized controlled trials. Devel Neurorehab, 18, 330–5.
Yoshimura, S, Uchida, K, Daimon, T, Takashima, R, Kimura, K, Morimoto, T; ASSORT Trial Investigator. (2017). Randomized controlled trial of early versus delayed statin therapy in patients with acute ischemic stroke: ASSORT Trial. Stroke, 48, 3057–63.
Zhang, J, Yang, J, Zhang, C, Jiang, X, Zhou, H, Liu, M. (2012). Calcium antagonists for acute ischemic stroke. Cochrane Database Syst Rev, 5. CD001928. doi:10.1002/14651858.CD001928.pub2.