Abstract
The identification of drugs targeting multiple pathways is essential for comprehensive protection against cerebral ischemia-reperfusion injury. This study aimed to develop RS31, a multi-target cytoprotectant composed of SS31 (an oxidative stress mitigator) and rapamycin (Rapa), contributes anti-inflammatory and blood-brain barrier protection. RS31 was synthesized using click chemistry, and its ability to scavenge reactive oxygen species (ROS) and reduce inflammation was tested in H2O2-injured PC12 cells and LPS-stimulated BV2 cells. A C57BL/6 mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) was established to assess the effect of RS31 on inflammatory factors in ischemic brain tissue. Finally, the potential of combining RS31 with PLGA microparticles (MPs) to further reduce brain edema was investigated. RS31 effectively scavenged ROS and reduced inflammation. It showed a ~ 4-fold higher concentration in cerebral ischemic regions, significant reducing infarction and improving neurological function. RS31 also effectively reduced inflammatory factors, lowered malondialdehyde (MDA) levels, and increased superoxide dismutase (SOD) activity, showing strong efficacy in treating ischemic stroke. In vivo delivery of RS31 is an effective therapeutic strategy for I/R injury, providing a general framework for developing multi-targeted drugs against inflammatory diseases and excessive ROS production.
Published Version
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