A Handbook of Clinical Neurology chapter (vol. 92, 2008; indexed as 2009;92:31-41) by Endres, Dirnagl, and Moskowitz assembled the ischemic cascade — the temporally evolving sequence of energy failure, excitotoxicity, peri-infarct depolarizations, oxidative and nitrosative stress, inflammation, and active cell-death programs that links arterial occlusion to brain tissue loss — and closed by identifying what remained unresolved: the timing and relative contribution of necrotic versus apoptosis-like death programs, whether peri-infarct depolarizations occur in and matter for human stroke, the net role and therapeutic timing of inflammation, translation of experimental mechanisms to human stroke subtypes, and the under-characterized white-matter component of ischemic injury. Since 2008, the occurrence of spreading depolarizations in human ischemic stroke has been demonstrated by direct subdural recording, while their therapeutic significance, the human in-vivo contribution of specific death programs, the timing of immunomodulation, and mechanism-based white-matter protection all remain open.

Background

Focal cerebral ischemia initiates a delayed, actively mediated sequence of injury known as the ischemic cascade: energy failure, glutamate release and overactivation of NMDA/AMPA receptors, calcium influx, radical and nitric-oxide-derived oxidant production, peri-infarct depolarizations, inflammatory amplification, and engagement of endogenous cell-death machinery. Tissue near the occluded artery dies (the core), while the surrounding penumbra — functionally silent but metabolically viable — can survive if perfusion is restored, and its progressive recruitment into the core defines the therapeutic problem. The chapter (Endres, Dirnagl, and Moskowitz, Handbook of Clinical Neurology vol. 92, 2008) synthesized this cascade and its mediators (excitotoxicity, nitric-oxide synthase isoforms, PARP-1 (poly(ADP-ribose) polymerase-1, a DNA-repair enzyme whose ischemic overactivation depletes cellular energy stores) activation, matrix metalloproteinases and neurovascular-unit failure, caspase-dependent and caspase-independent apoptosis-like death programs, ischemic preconditioning) almost exclusively from animal models. Peri-infarct depolarizations (PIDs) are transient, near-complete depolarizations of neurons and glia that arise in the core and repeatedly sweep the penumbra at roughly 1–4 events per hour in rodents, where their number correlates with, and causally enlarges, final infarct volume; the related phenomenon of spreading depression was first described by Leão in 1944. Before 2008, human evidence was essentially negative: repetitive diffusion-weighted MRI failed to detect PIDs in acute human stroke (Back et al., 2000), and direct recordings existed only in traumatically or surgically injured human cortex (Fabricius et al., 2006). The chapter therefore asked which parts of this experimentally defined cascade actually operate in — and can be therapeutically intercepted in — human embolic and thrombotic stroke and transient ischemic attack, noting that the human brain contains more than 50% white matter by volume whereas common rodent stroke models contain under about 10%, so white-matter (axonal and oligodendrocyte) injury, mediated in part by calcium-permeable AMPA receptors lacking the GluR2 subunit, was comparatively neglected. Subsequent methodological background: spreading depolarizations (SDs) are now recorded in neurocritical care by subdural electrocorticography (ECoG) during decompressive hemicraniectomy, coordinated by the Co-Operative Study on Brain Injury Depolarisations (COSBID); regulated necrosis forms such as necroptosis (a RIP1/RIP3 kinase-dependent, caspase-independent death program inhibitable by necrostatins, identified by Degterev et al. in 2005) and ferroptosis (iron-dependent lipid-peroxidative death) subsequently entered the stroke cell-death vocabulary; and neuroprotection trials targeting excitotoxicity signaling, such as nerinetide, an inhibitor of the postsynaptic scaffold protein PSD-95 that disrupts excitotoxic NMDA-receptor death signaling, have tested cascade-based translation in patients.

Problem Statement

For human ischemic stroke (embolic and thrombotic stroke and transient ischemic attack), determine which elements of the experimentally defined ischemic cascade operate in patients and where the cascade can be therapeutically intercepted. Concretely, as the source chapter formulated its unresolved issues: (i) establish the timing and relative contribution of the competing cell-death programs engaged after ischemia — coagulative necrosis versus apoptosis-like, caspase-dependent and caspase-independent (e.g. AIF-mediated) death programs — across ischemic severities and tissue compartments; (ii) establish whether peri-infarct depolarizations, demonstrated to enlarge infarcts in animal models, occur in human stroke and have biological and therapeutic significance there, i.e. whether suppressing them improves patient outcome; (iii) determine the net role of postischemic inflammatory and immune responses, which are both destructive and protective, including the cell types, mediators, and time window at which modulation should occur; and (iv) characterize white-matter (axonal and oligodendrocyte) ischemic injury at a mechanistic level commensurate with gray-matter injury, given its dominance in human brain volume. The four sub-questions are jointly required: the problem is resolved only when all four strands have been established in human stroke, and closing fewer leaves the translational core open. The experimental mechanisms must be linked to human stroke subtypes, replacing the current gap between animal-model knowledge and mechanism-based treatment design.

References

  1. Endres M, Dirnagl U, Moskowitz MA. Chapter 2 The ischemic cascade and mediators of ischemic injury. Handbook of Clinical Neurology. 2009;92:31-41. doi:10.1016/S0072-9752(08)01902-7. https://doi.org/10.1016/S0072-9752(08)01902-7
  2. Back T, Hirsch JG, Szabo K, Gass A. Failure to demonstrate peri-infarct depolarizations by repetitive MR diffusion imaging in acute human stroke. Stroke. 2000;31(12):2901-2906. doi:10.1161/01.STR.31.12.2901. https://doi.org/10.1161/01.STR.31.12.2901
  3. Fabricius M, Fuhr S, Bhatia R, Boutelle M, Hashemi P, Strong AJ, et al. Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain. 2006;129(Pt 3):778-790. doi:10.1093/brain/awh716. https://doi.org/10.1093/brain/awh716
  4. Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Reithmeier T, Ernestus RI, Brinker G, Dreier JP, Woitzik J, Strong AJ, Graf R; Co-Operative Study of Brain Injury Depolarisations (COSBID). Spreading depolarizations occur in human ischemic stroke with high incidence. Annals of Neurology. 2008;63(6):720-728. doi:10.1002/ana.21390. https://doi.org/10.1002/ana.21390
  5. Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, et al. The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy. Journal of Cerebral Blood Flow and Metabolism. 2017;37(5):1571-1594. doi:10.1177/0271678X16654495. https://doi.org/10.1177/0271678X16654495
  6. Pensato U, Ospel JM, Lemale CL, Hartings JA, Romoli M, Sacco S, Dreier JP. Spreading depolarization: A wave that precedes and drives cerebral ischemic cell death—Target for neuroprotection. Journal of Cerebral Blood Flow and Metabolism. 2026;46(7):1759-1781. doi:10.1177/0271678X261417186. https://doi.org/10.1177/0271678X261417186
  7. Sugimoto K, Nomura S, Shirao S, Inoue T, et al. Cilostazol decreases duration of spreading depolarization and spreading ischemia after aneurysmal subarachnoid hemorrhage. Annals of Neurology. 2018;84(6):873-885. doi:10.1002/ana.25361. https://doi.org/10.1002/ana.25361
  8. Degterev A, Huang Z, Boyce M, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology. 2005;1(2):112-119. doi:10.1038/nchembio711. https://doi.org/10.1038/nchembio711
  9. Chen Y, Zhang L, Yu H, et al. Necrostatin-1 improves long-term functional recovery through protecting oligodendrocyte precursor cells after transient focal cerebral ischemia in mice. Neuroscience. 2018;371:229-241. doi:10.1016/j.neuroscience.2017.12.007. https://doi.org/10.1016/j.neuroscience.2017.12.007
  10. Bautista-Perez SM, Silva-Islas CA, Sánchez-Thomas R, Figueroa A, Barrera-Oviedo D, Maldonado PD. Targeting ferroptosis and necroptosis to treat stroke. Neurochemical Research. 2026;51(2):135. doi:10.1007/s11064-026-04751-5. https://doi.org/10.1007/s11064-026-04751-5
  11. Emsley HCA, Smith CJ, Georgiou RF, et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. Journal of Neurology, Neurosurgery and Psychiatry. 2005;76(10):1366-1372. doi:10.1136/jnnp.2004.054882. https://doi.org/10.1136/jnnp.2004.054882
  12. Iadecola C, Buckwalter MS, Anrather J. Immune responses to stroke: mechanisms, modulation, and therapeutic potential. Journal of Clinical Investigation. 2020;130(6):2777-2788. doi:10.1172/JCI135530. https://doi.org/10.1172/JCI135530
  13. Hill MD, Goyal M, Menon BK, Nogueira RG, et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. The Lancet. 2020;395(10227):878-887. doi:10.1016/S0140-6736(20)30258-0. https://doi.org/10.1016/S0140-6736(20)30258-0
  14. Kremer R, Williams A, Wardlaw J. Endothelial cells as key players in cerebral small vessel disease. Nature Reviews Neuroscience. 2025;26(3):179-188. doi:10.1038/s41583-024-00892-0. https://doi.org/10.1038/s41583-024-00892-0