THE ROLE OF OXIDATIVE STRESS IN MICROCIRCULATORY NO-REFOW AFTER STROKE

Abstract

Recent clinical trials consistently show that despite successful recanalization, reperfusion of the ischemic tissue is often incomplete, whereas a favorable outcome is best correlated with satisfactory reperfusion. Incomplete reperfusion (no-reflow) is caused by loss of patency of some microvessels during ischemia, which persists after recanalization, limiting complete reperfusion of the ischemic tissue. Pericytes on microvessels play an important role in no-reflow by contracting during ischemia and remaining contracted after recanalization. Oxygen/nitrogen radicals were shown to contribute to pericyte injury and irreversible contraction, suggesting that prevention of microvascular changes induced by radical damage was essential for achieving effective reperfusion after recanalization and, hence, neuroprotection. Supporting the above view, a study from our laboratory found that blood-brain barrier (BBB)impermeable nitric oxide synthase inhibitor (L-N5-(1-iminoethyl)-ornithine; L-NIO) was equally neuroprotective to its BBB-permeable analog Nω-nitro-L-arginine [LNA] in a 2-hour middle cerebral artery occlusion model in the mouse. Indeed, L-NIO was shown to improve microcirculatory reperfusion after recanalization. A similar observation was made with N-tert-butyl-α-phenylnitrone (PBN) and its derivatives; SPBN, which is BBB-impermeable, was found to be equally well neuroprotective to PBN that is highly liposoluble. It appears so that promoting microvascular reperfusion by protecting vasculature against oxidative injury can alone provide neuroprotection. To directly investigate this hypothesis, we have recently developed an intra-vital imaging method that is specifically tailored to differentially monitor the postulated actions of anti-oxidant treatments at parenchymal and vascular compartments in vivo by using a fluorescent probe or transgenic mice expressing oxygen radical sensitive fluorescent reporter. Our findings illustrate that suppressing oxygen radical toxicity on the vascular wall alone can improve reperfusion after recanalization and provide neuroprotection against focal cerebral ischemia.

Keywords: Cerebral ischemia, reperfusion, oxygen radicals, antioxidants, neuroprotection.