Reversible vs. Irreversible Neuronal Injury in Brain Ischemia: Role of the Mitochondrial–Synaptic Axis

초록

Ischemia-reperfusion (I/R) injury triggers a rapid and self-amplifying cascade of mitochondrial dysfunction, synaptic instability, and neuroinflammation that ultimately determines neuronal survival and functional recovery. Early bioenergetic collapse—driven by mitochondrial depolarization, Reactive oxygen species (ROS) overproduction, and impaired mitophagy—initiates excitotoxic signaling and calpain-mediated structural degradation at vulnerable synapses. These events converge with microglial and astrocytic activation to exacerbate cytokine release, blood-brain barrier (BBB) disruption, and delayed neuronal injury. Therapeutic strategies targeting this axis show considerable promise. Mitochondria-directed interventions—including mitophagy modulation, Dynamin-related protein 1 (Drp1) inhibition, antioxidant nanocarriers, and emerging mitochondrial transplantation—restore Adenosine triphosphate (ATP) production, stabilize membrane potential, and prevent downstream excitotoxic injury. Synaptic protection via N-methyl-D-aspartate (NMDA)/postsynaptic density protein-95 (PSD-95) uncoupling, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor stabilization, and calpain inhibition preserves dendritic architecture and neurotransmission. Modulation of inflammatory pathways, particularly Interleukin-1 β (IL-1 β), Tumor necrosis factor- α (TNF- α), and Interleukin-6 (IL-6) signaling, as well as cell-specific microglial and astrocytic reprogramming, further attenuates secondary degeneration. Gene- and RNA-based therapies, nanoparticles engineered for BBB penetration, and extracellular vesicle-mediated delivery systems represent additional advanced platforms moving toward clinical translation. Despite substantial progress, challenges remain, including timing constraints, region-specific vulnerability (e.g., CA1 vs. CA3), limited BBB permeability, and species differences in mitochondrial dynamics and glial responses. Integrative multimodal strategies—combining mitochondrial repair, synaptic stabilization, and immunomodulation—along with advanced imaging, spatial transcriptomics, and patient-derived organoids, may accelerate the development of precision therapies for I/R injury. This review synthesizes mechanistic and translational evidence demonstrating that the mitochondria-synapse-inflammation axis forms a unified pathological framework across experimental and clinical I/R settings, including transient focal ischemia, global ischemia following cardiac arrest (CA), and reperfusion after thrombolysis or thrombectomy. © 2026 The Author(s). Published by IMR Press. This is an open access article under the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/

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