Cover Story | Solving the Challenge of Deep Hypothermic Brain Protection: Unveiling a Novel Mechanism of White Matter Injury
Release time:
2026-06-26
Hypothermia has long been a critical tool in clinical practice for combating hypoxic-ischemic brain injury. Particularly in complex congenital heart disease surgeries, deep hypothermic circulatory arrest (DHCA) provides surgeons with valuable operating time while shielding the vulnerable developing brain. However, this protection is not foolproof—even under hypothermic conditions, the developing brain can still sustain white matter injury, which poses a long-term risk to cognitive and motor function in affected children.
White matter serves as a vital medium for neural signal transmission in the brain, and the integrity of myelin directly determines the efficiency of information conduction. Once myelin is damaged, irreversible neurological dysfunction may ensue. For years, the questions have remained unresolved: Why does white matter injury still occur after hypothermic protection? What are the key cellular and molecular mechanisms behind it? And how can we effectively intervene?
In June 2026, Neuroscience Bulletin published a collaborative study as its cover article, titled "Microglia Pyroptosis-Derived IL-18 Drives White Matter Injury in Developing Brain following Hypothermic Hypoxia-Ischemia." This study is the first to systematically elucidate the core mechanism of white matter injury in the developing brain after hypothermic hypoxia-ischemia, and it proposes a highly translational "drug repurposing" intervention strategy, offering a fresh approach to neuroprotection following complex congenital heart surgery.
The research team first focused on clinical imaging evidence: Magnetic resonance imaging (MRI) analyses of children who underwent cardiopulmonary bypass (CPB) or DHCA revealed punctate lesions in the periventricular white matter and reduced white matter fiber tract numbers in the DHCA group. Diffusion tensor imaging (DTI) further indicated a significant decrease in fractional anisotropy (FA)—all hallmark imaging features of white matter injury.
To investigate the underlying causes, the team turned to the brain's immune "sentinels"—microglia. Using a weanling rat model of hypothermic hypoxia-ischemia, ex vivo brain slice cultures, and a DHCA surgical model, the study found that hypothermic hypoxia-ischemia markedly activated microglia and triggered their specific inflammatory form of cell death—pyroptosis. This process was mediated by the NF-κB signaling pathway, driving massive expression of the pyroptosis-executing protein Gasdermin D (GSDMD), which ultimately led to the release of large amounts of the pro-inflammatory cytokine IL-18 from microglia. This, in turn, disrupted myelin architecture and induced white matter injury. Three-dimensional reconstructions clearly showed enhanced IL-18 signals within pyroptotic microglia, directly confirming their role as the "source of inflammation."
Based on this mechanism, the team further explored intervention strategies. Encouragingly, disulfiram (DSF)—a commonly used clinical anti-alcoholism drug—demonstrated unexpected benefits in the experiments: administration of disulfiram in DHAC model rats effectively suppressed microglial pyroptosis, significantly alleviated myelin damage, and markedly preserved white matter structure. The "drug repurposing" approach offers a low-cost, highly feasible new direction for the development of clinical neuroprotective agents.
This study not only fills a critical mechanistic gap in the field of hypothermic brain protection but also provides precise therapeutic targets for the prevention and treatment of white matter injury after complex congenital heart surgery.
Paper Information: Microglia Pyroptosis-Derived IL-18 Drives White Matter Injury in Developing Brain following Hypothermic Hypoxia-Ischemia. Neuroscience Bulletin (2026). Cover Article.
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