Ischemic Neuronal Injury Mechanisms

Ischaemic neuronal injury arises when cerebral blood flow is acutely reduced or arrested, leading to a cascade of interlinked biochemical and cellular events. Energy depletion rapidly impairs ion-pump function, provoking membrane depolarisation, dysregulated calcium influx and release of excitatory neurotransmitters. Glutamate-mediated excitotoxicity amplifies calcium overload, activating degradative enzymes and promoting mitochondrial dysfunction. Concurrent generation of reactive oxygen and nitrogen species damages lipids, proteins and nucleic acids, while iron-dependent lipid peroxidation may precipitate ferroptotic cell death. Endoplasmic reticulum stress and activation of the ubiquitin-proteasome system further compromise proteostasis, triggering pro-apoptotic signalling mediated by factors such as p53 and PUMA. Inflammatory responses, driven by activated microglia and invading leukocytes, release cytokines and matrix metalloproteinases that disrupt the neurovascular unit and exacerbate blood–brain barrier permeability. Within hours to days of reperfusion, selective populations of neurons—most notably hippocampal CA1 pyramidal cells—undergo delayed degeneration. Emerging data highlight the interplay between metabolic reprogramming, synaptic plasticity alterations and vascular dysfunction, underscoring multiple potential targets for therapeutic intervention and the global importance of mitigating stroke-related disability.

Research from Nature Portfolio

Recent studies have delineated the central role of ferroptosis regulators in ischaemic stroke. One investigation demonstrated that inhibition of lipid peroxidation enzymes reduces neuronal death in both in vitro oxygen–glucose-deprivation models and in vivo transient middle cerebral artery occlusion, pinpointing acyl-CoA synthetase long-chain family member 4 as a therapeutic node. A complementary study characterised how acute disruption of endothelial–pericyte contacts within the neurovascular unit provokes vascular leakage and amplifies excitotoxic cascades, and showed that stabilising pericyte signalling attenuates infarct size and preserves synaptic integrity.

Ischemic Neuronal Injury Mechanisms publication trend

The graph below shows the total number of articles in ischemic neuronal injury mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Excitotoxicity: Neuronal damage caused by excessive activation of glutamate receptors leading to calcium overload.

Ferroptosis: Iron-dependent form of cell death driven by lipid peroxidation.

Endoplasmic reticulum stress: Cellular condition arising from accumulation of misfolded proteins in the ER lumen.

Proteostasis: Balance of protein synthesis, folding and degradation mechanisms within the cell.

Neurovascular unit: Functional ensemble of neurons, glia, endothelial cells and pericytes that maintains the blood–brain barrier and cerebral homeostasis.

References

1. An Electrophysiological and Proteomic Analysis of the Effects of the Superoxide Dismutase Mimetic, MnTMPyP, on Synaptic Signalling Post-Ischemia in Isolated Rat Hippocampal Slices. Antioxidants (2023).
2. Dihydropyrimidinase-Related Protein 2 Is a New Partner in the Binding between 4E-BP2 and eIF4E Related to Neuronal Death after Cerebral Ischemia. International Journal of Molecular Sciences (2023).
3. Involvement of Proteasomal and Endoplasmic Reticulum Stress in Neurodegeneration After Global Brain Ischemia. Molecular Neurobiology (2023).