Abstract
Inhaled argon (iAr) has shown promising therapeutic efficacy for acute ischemic stroke and has exhibited impressive advantages over other inert gases as a neuroprotective agent. However, the optimal dose, duration, and time point of iAr for acute ischemic stroke are unknown. Here, we explored variable iAr schedules and evaluated the neuroprotective effects of acute iAr administration on lesion volume, brain edema, and neurological function in a mouse model of cerebral ischemic/reperfusion injury. Adult ICR (Institute of Cancer Research) mice were randomly subjected to sham, moderate (1.5h), or severe (3h) transient middle cerebral artery occlusion (tMCAO). One hour after tMCAO, the mice were randomized to variable iAr protocols or air. General and focal deficit scores were assessed during double-blind treatment. Infarct volume, overall recovery, and brain edema were analyzed 24h after cerebral ischemic/reperfusion injury. Compared with those in the tMCAO-only group, lesion volume (p < 0.0001) and neurologic outcome (general, p < 0.0001; focal, p < 0.0001) were significantly improved in the group administered iAr 1h after stroke onset (during ischemia). Short-term argon treatment (1 or 3h) significantly improved the infarct volume (1 vs. 24h, p < 0.0001; 3 vs. 24h, p < 0.0001) compared with argon inhalation for 24h. The concentration of iAr was confirmed to be a key factor in improving focal neurological outcomes relative to that in the tMCAO group, with higher concentrations of iAr showing better effects. Additionally, even though ischemia research has shown an increase in cerebral damage proportional to the ischemia time, argon administration showed significant neuroprotective effects on infarct volume (p < 0.0001), neurological deficits (general, p < 0.0001; focal, p < 0.0001), weight recovery (p < 0.0001), and edema (p < 0.0001) in general, particularly in moderate stroke. Timely iAr administration during ischemia showed optimal neurological outcomes and minimal infarct volumes. Moreover, an appropriate duration of argon administration was important for better neuroprotective efficacy. These findings may provide vital guidance for using argon as a neuroprotective agent and moving to clinical trials in acute ischemic stroke.
Highlights
Acute ischemic stroke (AIS) is a major global disease characterized by a high incidence, disability rate and mortality rate and is one of the main reasons for admission to the neurological intensive care unit[1, 2]
To assess whether argon treatment at different initiation points has neuroprotective effects after severe ischemic stroke induced by delayed reperfusion (I/R; 3 h/24 h) and to explore the best time point for Inhaled argon (iAr) administration, we applied two different treatment strategies that are closer to the actual clinical situation
We found that in the total infarct volume analysis, the group that inhaled argon 1 h after stroke onset showed significantly lower volumes 24 h after reperfusion than the transient middle cerebral artery occlusion (tMCAO) alone group, and a significant difference was observed between the two argon treatment groups. (Fig. 2B; P < 0.001)
Summary
Acute ischemic stroke (AIS) is a major global disease characterized by a high incidence, disability rate and mortality rate and is one of the main reasons for admission to the neurological intensive care unit[1, 2]. Inhaled argon (iAr) has become a promising choice due to encouraging neuroprotective effects demonstrated in multiple species and a range of experimental models of stroke, hypoxic-ischemic encephalopathy (HIE) and trauma[8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23], with the unique advantages of being readily available, easy to administer and transport, lacking anesthetic properties under normal pressure and not inhibiting the thrombolytic efficacy of tissue plasminogen activators at high concentrations (75%)[24,25,26,27,28,29]. We explored variable iAr schedules and evaluated the neuroprotective effects of acute iAr administration on lesion volume, brain edema, and neurological function in a mouse model of cerebral ischemic/reperfusion (I/R) injury
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