Detection of lipid radicals generated via cerebral ischemia/reperfusion injury using a radiolabeled nitroxide probe

Reactive oxygen species generated via reperfusion cause lipid damage and induce lipid peroxidation, leading to cerebral ischemia/reperfusion injury and exacerbation of cerebral infarction. Lipid radicals are key molecules generated during lipid peroxidation. Therefore, understanding the spatiotemporal behavior of lipid radicals is important to improve the therapeutic outcomes of cerebral infarction. However, the behaviors of lipid radicals in the brain remain unclear. In this study, we aimed to evaluate the distribution of radioactivity in a transient middle cerebral artery occlusion (tMCAO) model using lipid radical detection probe [¹²⁵I]1 to assess the behaviors of lipid radicals after cerebral ischemia/reperfusion. The tMCAO model administered [¹²⁵I]1 exhibited significant differences in the timing and location of radioactivity accumulation between the ischemic and non-ischemic regions. Liquid chromatography/mass spectrometry analysis identified the lipid radical adducts formed by the reaction of 1 with the lipid radicals generated after reperfusion. More adducts were detected in the ischemic region samples than in the non-ischemic region samples. Therefore, 1 successfully detected the lipid radicals generated after cerebral ischemia/reperfusion. Overall, this study demonstrates the potential of nuclear medical imaging using radiolabeled 1 to detect the lipid radicals generated after cerebral ischemia/reperfusion. Our approach can aid in the development of new therapeutic agents scavenging lipid radicals after cerebral reperfusion by facilitating the determination of therapeutic efficacy and optimal administration period.