Argon as a Stabilizer of the Neurovascular Unit in Ischemia-reperfusion Injury: A Narrative Review

Dysfunction of the Neurovascular Unit (NVU) represents a common pathway of injury in ischemia-reperfusion and critical illness. Disruption of blood-brain barrier integrity, microcirculatory reperfusion heterogeneity, and neuroinflammation synergistically amplify secondary neural damage. In this context, attention is increasingly being directed toward interventions that stabilize the NVU as an integrated system rather than targeting neurons alone. This review aimed to summarize and critically appraise the evidence on the beneficial effects of argon in experimental models of ischemia-reperfusion and related critical scenarios, with emphasis on the hierarchy of evidence.

A focused narrative review was conducted by searching major bibliographic databases through December 2025, followed by manual selection of relevant studies and citation tracking. The SANRA checklist was applied for internal quality control of the narrative review. Statements were structured according to level of evidence ("demonstrated," "indirectly supported," and "not demonstrated") and linked to model type, therapeutic time windows, and outcome measures. A total of 110 references were included.

The strongest body of evidence concerns the neuroimmune compartment. Argon attenuates microglial activation and suppresses pro-inflammatory cascades, including inflammasomerelated signaling, thereby reducing pyroptotic markers. In the neuronal compartment, argon is associated with pro-survival shifts, including modulation of the Bcl-2 family balance, reduced caspase-3 activity, and partial preservation of mitochondrial membrane potential. By contrast, microcirculatory improvement is documented mainly at the level of integrated outcomes, such as perfusion, cerebral blood flow, and neurological performance.

However, the underlying cellular mechanisms involving endothelial cells, pericytes, and microthromboinflammation remain insufficiently characterized. Direct evidence regarding tight junction proteins, matrix metalloproteinases, and endothelial nitric oxide signaling under argon exposure is limited, indicating a clear asymmetry in mechanistic resolution across NVU compartments.

Current evidence supports argon as a promising NVU-oriented neuroprotective modulator, with the strongest support for neuroimmune mechanisms. Evidence for barrierrelated and microcirculatory mechanisms remains limited and requires direct validation in future studies.