Transarterial Regional Brain Hypothermia Inhibits Acute Aquaporin-4 Surge and Sequential Microvascular Events in Ischemia/Reperfusion Injury.

Abstract

Although transarterial regional hypothermia is an attractive alternative to general hypothermia, its efficacy and underlying mechanisms remain unclear. To confirm transarterial regional hypothermia therapeutic effects on ischemia/reperfusion (I/R) injury and to elucidate the mechanisms responsible. The therapeutic effects of transarterial regional hypothermia were initially investigated in 2-hour middle cerebral artery occlusion rats regionally infused with 10°C saline (cold saline group) or 37°C saline (warm saline group) and untreated rats (control group) just before the onset of 24 hours of reperfusion. The time course of infarct and edema progression, inflammatory reactions, microvascular morphological changes, and aquaporin-4 (AQP4) expression was analyzed after 0, 2, 6, and 24 hours of reperfusion. Cold saline infusion only lowered brain temperatures for 30 minutes but mediated strong neuroprotective effects with infarct volume reductions of less than one-third. The time-course analysis revealed the following sequence of ischemia/reperfusion injury-related events in the control group: upregulated expression of AQP4 (2 hours); microvascular narrowing resulting from swollen astrocytic end-feet (2-6 hours); infarct and edema progression, blood-brain barrier disruption, and upregulated expression of intracellular adhesion molecule-1 (6-24 hours); and the activation of other inflammatory reactions (24 hours). These sequential events were inhibited in the cold saline group. Transarterial regional hypothermia initially inhibited the acute AQP4 surge and then attenuated microvascular narrowing, blood-brain barrier disruption, and activation of other inflammatory reactions, leading to strong neuroprotective effects. More direct and intensive cooling of the endothelium and its surroundings may contribute to these effects. AQP4, aquaporin-4BBB, blood-brain barrierIba1, ionized calcium-binding adapter molecule 1ICA, internal carotid arteryICAM-1, intracellular adhesion molecule-1I/R, ischemia/reperfusionMCAO, middle cerebral artery occlusionMMP-9, matrix metalloproteinase-9.