title: Newly synthesized radical-containing nanoparticles enhance neuroprotection after cerebral ischemia-reperfusion injury.
abstract: 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.
  
  
  CONCLUSIONS
  RNPs could be a promising neuroprotective agent with their enhanced ability to scavenge free radicals and reduced toxicity.
authors.affiliation: Department of Neurosurgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Aiki
authors.initials: A
authors.lastname: Marushima
authors.forename: Kensuke
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nagasaki
authors.forename: Toru
authors.initials: T
authors.lastname: Yoshitomi
authors.forename: Kazuko
authors.initials: K
authors.lastname: Toh
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsurushima
authors.forename: Aki
authors.initials: A
authors.lastname: Hirayama
authors.forename: Akira
authors.initials: A
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000008:administration & dosage* / Q000138:chemical synthesis; D004337:Drug Carriers / Q000008:administration & dosage / Q000138:chemical synthesis; D004357:Drug Synergism; D005609:Free Radicals / Q000008:administration & dosage / Q000138:chemical synthesis; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D013113:Spin Labels / Q000138:chemical synthesis
chemical_list: D003497:Cyclic N-Oxides; D004337:Drug Carriers; D005609:Free Radicals; D018696:Neuroprotective Agents; D013113:Spin Labels; C003959:TEMPO