Targeting Blood-Brain Barrier Leakage for Visualizing, Monitoring, and Evaluating Ischemia Reperfusion Injury with Rus-Tc ^99m Probe

Abstract

Cerebral ischemia-reperfusion (I/R) injury as a serious threat to human health is characterized by cerebral endothelial leakage, as a result of the damage of blood-brain barrier (BBB). It is thus quite attractive to realize real-time monitoring of BBB damage for therapeutic surveillance. In this study, a radioactive probe is constructed by conjugating ruscogenin (Rus), a neuroprotectants, to technetium-99m (Tc^99m) to assess the damage of cerebral endothelial in BBB. In vitro study proves that the probe can penetrate more efficiently in damaged BBB. Then, longitudinal nuclear imaging distinguishes mice with BBB leakage from normal ones, which is validated by evans blue staining of brain tissue. Higher nuclear signal also correlates with poorer blood circulation in brain. Further, by visualizing brain signal during drug treatment, the probe finds that the most obvious protective efficacy of Rus occurs at 12 h post administration, which is superior than edaravone (Edara). Altogether, the probe is promising to monitor I/R injury real-time by radioactive-imaging of BBB integrity. Importantly, Rus as a neuroprotectants may serve as a potential theranostic agent for I/R treatment.

Funding Statement: This research was supported by funding from the National Natural Science Foundation of the People’s Republic of China (NO. 81773971), the 2018 Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education(SJKY19-0657), and the “Double First-Class” University project(CPU2018GF07).

Declaration of Interests: All the authors declare no potential conflict of interest.

Ethics Approval Statement: All procedures and assessments were approved by the Animal Ethics Committee of the School of Chinese Materia Medica, China Pharmaceutical University.