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Newly Synthesized Radical-Containing Nanoparticles Enhance Neuroprotection After Cerebral Ischemia-Reperfusion Injury

BACKGROUND:Antioxidant nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) have been investigated for their ability to scavenge free radicals produced by ischemia-reperfusion injury. However, the short in vivo half-life and toxicity of TEMPO have limited their clinical application. OBJECTIVE:We developed a core-shell-type nanoparticle, termed a radical-containing nanoparticle (RNP), to deliver nitroxyl radicals with prolonged in vivo half-life and pH-sensitivity. We evaluated the ability of RNP to deliver TEMPO radicals to the ischemic brain and scavenge free radicals in cerebral ischemia-reperfusion injury using rats. METHODS:When RNPs were administrated to middle cerebral artery occlusion rats, the delivery and clearance of RNPs were detected using electron paramagnetic resonance (EPR) assay. The production of superoxide anion in neuronal cells was observed with dihydroethidium staining. The treatment effects were evaluated by measuring the cerebral infarction volumes, lipid peroxidation and protein oxidation, and neurological symptom scoring. RESULTS:The TEMPO radicals contained in RNPs were detected for 6 hours after intravenous administration as a triplet EPR signal in the ischemic brain, and RNPs significantly reduced the production of superoxide anion in neuronal cells compared with saline and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyls (TEMPOL). The infarction volumes of rats treated by RNPs were significantly lower than those of rats treated by saline, micelles, and TEMPOL. In addition, RNP treatment suppressed lipid peroxidation and protein oxidation, and limited the adverse effects of TEMPO radicals such as hypotension. CONCLUSION:RNPs could be a promising neuroprotective agent with their enhanced ability to scavenge free radicals and reduced toxicity.