Platinum-Loaded Cerium Oxide Capable of Repairing Neuronal Homeostasis for Cerebral Ischemia-Reperfusion Injury Therapy.

Abstract

Effective neuroprotective agents are required to prevent neurological damage caused by reactive oxygen species (ROS) generated by cerebral ischemia-reperfusion injury (CIRI) following an acute ischemic stroke. Herein, it is aimed to develop the neuroprotective agents of cerium oxide loaded with platinum clusters engineered modifications (Pt_n-CeO₂). The density functional theory calculations show that Pt_n-CeO₂ could effectively scavenge ROS, including hydroxyl radicals (·OH) and superoxide anions (·O₂ ^-). In addition, Pt_n-CeO₂ exhibits the superoxide dismutase- and catalase-like enzyme activities, which is capable of scavenging hydrogen peroxide (H₂O₂). The in vitro studies show that Pt_n-CeO₂ could adjust the restoration of the mitochondrial metabolism to ROS homeostasis, rebalance cytokines, and feature high biocompatibility. The studies in mice CIRI demonstrate that Pt_n-CeO₂ could also restore cytokine levels, reduce cysteine aspartate-specific protease (cleaved Caspase 3) levels, and induce the polarization of microglia to M2-type macrophages, thus inhibiting the inflammatory responses. As a result, Pt_n-CeO₂ inhibits the reperfusion-induced neuronal apoptosis, relieves the infarct volume, reduces the neurological severity score, and improves cognitive function. Overall, these findings suggest that the prominent neuroprotective effect of the engineered Pt_n-CeO₂ has a significant neuroprotective effect and provides a potential therapeutic alternative for CIRI.