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Peer-reviewedCC BY 4.0Frontiers in Immunology

Brain cytoprotection in acute ischemic stroke in the reperfusion era: neuroimmune networks, clinical evidence, and translational barriers

  • Xue Gao1
  • Shanshan Tong2
  • Xiaonan Wang3
  • Xuan Zhou4
  • Qiong Chen5
  • Jinxiang Wang6
  • Fan Wu7
7 affiliations
  1. 1Department of Neurology, Anhui No.2 Provincial People’s Hospital
  2. 2Faculty of Chinese Medicine, Macau University of Science and Technology
  3. 3Quality Control Office, Anhui No.2 Provincial People’s Hospital
  4. 4Research and Education Office, Guilin Municipal Hospital of Traditional Chinese Medicine
  5. 5Department of Medical Laboratory Center, Anhui No.2 Provincial People’s Hospital
  6. 6Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University
  7. 7Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University
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Abstract

Intravenous thrombolysis and mechanical thrombectomy have transformed acute ischemic stroke (AIS) care, yet angiographic recanalization does not guarantee adequate tissue reperfusion or long-term functional independence. Brain cytoprotection has therefore expanded from neuron-centered rescue to preservation of the ischemic penumbra, neurovascular unit, blood-brain barrier (BBB), and microcirculation. Using a systems-immunology perspective, this clinically oriented narrative review examines ischemia-reperfusion injury as a dynamic network linking danger-associated molecular pattern sensing, microglia and astrocytes, circulating leukocytes, platelets and complement, endothelium and pericytes, cytokine signaling, edema, no-reflow, and regulated cell-death programs. We integrate classic and recent evidence for excitotoxic, redox and mitochondrial, inflammatory, barrier, microvascular, and cell-death targets; evaluate representative pharmacologic and nonpharmacologic interventions; and distinguish negative primary endpoints from exploratory subgroup or surrogate signals. Confirmatory excitotoxicity trials have remained negative overall. Selected multitarget agents have shown benefit in specific Chinese populations, whereas immune-, edema-, and no-reflow-directed approaches have yielded stage-specific but inconsistent safety, imaging, and functional results. Statins, nitric oxide donors, and phosphodiesterase inhibition have plausible vascular or immunomodulatory actions, but available trials do not establish them as acute cytoprotective therapies. Future development should align the right mechanism, tissue phenotype, treatment time, exposure, target-engagement measure, and patient-centered endpoint, followed by multicenter preclinical testing and independent cross-regional clinical replication. This end-to-end framework reframes brain cytoprotection as precision modulation of a spatially and temporally evolving neuroimmune-vascular system rather than a single undifferentiated treatment class.

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Cite

BibTeXRIS
BibTeX
@article{gao2026brain,
  title = {{Brain cytoprotection in acute ischemic stroke in the reperfusion era: neuroimmune networks, clinical evidence, and translational barriers}},
  author = {Xue Gao and Shanshan Tong and Xiaonan Wang and Xuan Zhou and Qiong Chen and Jinxiang Wang and Fan Wu},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1984227},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1984227/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Brain cytoprotection in acute ischemic stroke in the reperfusion era: neuroimmune networks, clinical evidence, and translational barriers
AU  - Xue Gao
AU  - Shanshan Tong
AU  - Xiaonan Wang
AU  - Xuan Zhou
AU  - Qiong Chen
AU  - Jinxiang Wang
AU  - Fan Wu
PY  - 2026
DA  - 2026/10/21
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1984227
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1984227/full
AB  - Intravenous thrombolysis and mechanical thrombectomy have transformed acute ischemic stroke (AIS) care, yet angiographic recanalization does not guarantee adequate tissue reperfusion or long-term functional independence. Brain cytoprotection has therefore expanded from neuron-centered rescue to preservation of the ischemic penumbra, neurovascular unit, blood-brain barrier (BBB), and microcirculation. Using a systems-immunology perspective, this clinically oriented narrative review examines ischemia-reperfusion injury as a dynamic network linking danger-associated molecular pattern sensing, microglia and astrocytes, circulating leukocytes, platelets and complement, endothelium and pericytes, cytokine signaling, edema, no-reflow, and regulated cell-death programs. We integrate classic and recent evidence for excitotoxic, redox and mitochondrial, inflammatory, barrier, microvascular, and cell-death targets; evaluate representative pharmacologic and nonpharmacologic interventions; and distinguish negative primary endpoints from exploratory subgroup or surrogate signals. Confirmatory excitotoxicity trials have remained negative overall. Selected multitarget agents have shown benefit in specific Chinese populations, whereas immune-, edema-, and no-reflow-directed approaches have yielded stage-specific but inconsistent safety, imaging, and functional results. Statins, nitric oxide donors, and phosphodiesterase inhibition have plausible vascular or immunomodulatory actions, but available trials do not establish them as acute cytoprotective therapies. Future development should align the right mechanism, tissue phenotype, treatment time, exposure, target-engagement measure, and patient-centered endpoint, followed by multicenter preclinical testing and independent cross-regional clinical replication. This end-to-end framework reframes brain cytoprotection as precision modulation of a spatially and temporally evolving neuroimmune-vascular system rather than a single undifferentiated treatment class.
SN  - 1664-3224
ER  -