Edaravone, a potent free radical scavenger, has been used clinically in Japan since 2001 for the treatment of acute brain infarction,
15 but there is no evidence of neuroprotective effect in ocular ischemic syndrome. On the other hand, a large number of patients with ocular ischemic syndrome present with a history of previous stroke or transient ischemic attack.
23,24 Severe carotid artery stenosis or occlusion associated with atherosclerosis is a common cause of ocular ischemic syndrome and stroke. Thus, prolonged disturbance in the blood supply to the brain or retina commonly induces irreversible neuronal death. Furthermore, we have reported that edaravone can protect against brain infarction in a mouse model of cerebral ischemia
25 and retinal cell death in a mouse model of excitatory amino acid–induced retinal injury.
26 Mizuno et al.
27 have reported that thrombotic occlusion of rat middle cerebral artery increases hydroxyl radical at the ischemic border zone, and its production is attenuated by edaravone. We investigated the expression of 8-hydroxy-2-deoxyguanosine (8-OHdG), which is produced by hydroxyl radical (data not shown). Five-hour ligation of PPA and ECA markedly increased 8-OHdG-positive cells in the GCL and INL at 7 and 19 hours after reperfusion. These data strongly suggest that oxidative stress is increased in the retina in the ocular ischemia model, as in the stroke model. In the present study we used edaravone for evaluating drugs targeting ocular ischemic diseases without affecting blood flow. The improvement of reduced blood flow using calcium channel blockers or antiplatelet agents may be effective in this model, but edaravone did not affect normal vessel diameters of retinal central arteries or veins. Moreover, it has been reported that edaravone does not affect blood pressure, heart rate, or cerebral blood flow.
13 In the present study, edaravone displayed significant protective effects against retinal ischemic damage induced by ligation of the PPA and the ECA. On the other hand, edaravone markedly protected the reduction of b-waves, but not a-waves, after ocular ischemia. In the present ocular ischemic model, 5-hour ischemia followed by 5 days of reperfusion strongly reduced the amplitude of the b-wave, but reduction of the a-wave amplitude was mild. These results can be explained by the fact that INL neurons, which reflect b-wave amplitudes, are more susceptible to ischemia than ONL neurons
28,29 and that ONL cells, whose function was reflected by the a-wave, are less sensitive to ischemic damage. The present study also indicates that the inner retina was sensitively damaged by ligating PPA and ECA. Because there was a mild reduction of a-wave amplitude after retinal ischemia, the ameliorative effect of edaravone against a-wave amplitudes could not be detected statistically. Taken together, these findings indicate that oxidative stress plays a pivotal role in the mechanism of retinal damage in the retinal ischemia model.