Cyanine Dyes Attenuate Cerebral Ischemia and Reperfusion Injury in Rats

Some photosensitizing cyanine dyes act on the immune system to enhance the phagocytic capacity of macrophages. In this study, we examined whether these dyes have neurotrophin-like activities and neuroprotective effects in vitro and in vivo. By screening more than 250 cyanine dyes, we found that NK-4 and NK-150, which belong to a group of pentamethine trinuclear cyanine dyes, significantly potentiated nerve growth factor (NGF)-primed neurite outgrowth of PC12HS cells in nanomolar to micromolar concentrations. Both NK-4 and NK-150 showed a remarkable hydroxyl radical-scavenging activity using an in vitro electron spin resonance (ESR)-based technique. They also effectively scavenged peroxy radicals, and in addition, NK-4 acted on superoxides to a similar extent as ascorbate. In vivo, NK-4 and NK-150 prevented cerebral ischemic injury induced by 2 h middle cerebral artery occlusion (MCAO) and 24 h reperfusion in rats. Dyes were intravenously administrated twice 1 h after the occlusion and immediately after the start of reperfusion. NK-4 and NK-150 (100 µg/kg) reduced cerebral infarct volumes by 57.0% and 46.0%, respectively. Those dyes also decreased brain swelling in the ischemic semispheres. As a result, administration of NK-4 and NK-150 provided substantial improvements in MCAO-induced neurological deficits in a dose-dependent manner. These results suggest that NK-4 and NK-150 effectively prevented ischemia-induced brain injury through their potent neurotrophin-like activity as well as antioxidative activity.