Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

Med Res Rev. 2022 Jan;42(1):259-305. doi: 10.1002/med.21817. Epub 2021 May 6.


Ischemic stroke caused by arterial occlusion is the most common type of stroke, which is among the most frequent causes of disability and death worldwide. Current treatment approaches involve achieving rapid reperfusion either pharmacologically or surgically, both of which are time-sensitive; moreover, blood flow recanalization often causes ischemia/reperfusion injury. However, even though neuroprotective intervention is urgently needed in the event of stroke, the exact mechanisms of neuronal death during ischemic stroke are still unclear, and consequently, the capacity for drug development has remained limited. Multiple cell death pathways are implicated in the pathogenesis of ischemic stroke. Here, we have reviewed these potential neuronal death pathways, including intrinsic and extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, and pyroptosis. We have also reviewed the latest results of pharmacological studies on ischemic stroke and summarized emerging drug targets with a focus on clinical trials. These observations may help to further understand the pathological events in ischemic stroke and bridge the gap between basic and translational research to reveal novel neuroprotective interventions.

Keywords: apoptosis; ferroptosis; ischemic stroke; neuronal death; neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis
  • Brain Ischemia* / drug therapy
  • Cell Death
  • Humans
  • Ischemic Stroke*
  • Neuroprotection
  • Neuroprotective Agents* / pharmacology
  • Neuroprotective Agents* / therapeutic use
  • Stroke* / drug therapy


  • Neuroprotective Agents