Abstract
Background and aims: Despite early aneurysm repair and aggressive management for complications, subarachnoid hemorrhage (SAH) results in at least 25% mortality rate and 50% persistent neurologic deficit. Thus, a novel therapeutic agent that directly targets brain damages after SAH is strongly required. For this purpose, we developed aminocaproic acid stabilized ceria nanoparticles (Amicar-CeNPs), which have incomparable anti-oxidative activity and biocompatibility. Methods: Uniform water-dispersed Amicar-CeNPs were prepared from short sol-gel reaction of cerium (III) ions in aqueous phase with aminocaproic acid. SAH was induced by endovascular perforation of middle cerebral artery of rats. A single dose of Amicar-CeNPs (0.5mg/kg) or saline control were randomly administered intravenously at an hour post-SAH. Neuronal death, macrophage infiltration, SAH grade and brain water content were evaluated at 72 hours. Mortality and neurologic function were assessed for 14 days. Results: Amicar-CeNPs, 3-nm in size and with high Ce 3+ to Ce 4+ ratio, demonstrated very potent anti-oxidative, cytoprotective, and anti-inflammatory activities in vitro. In rodent SAH model, Amicar-CeNPs significantly reduced neuronal death (1.1% vs. 90.1%; P<0.01), macrophage infiltration (74 vs. 188; P<0.01) and brain water content (80.2% vs. 80.7%; P<0.05) 72 hours post-SAH as compared with the saline control. SAH grades were comparable between the two groups (13.1±1.7 vs. 12.3±2.6). Amicar-CeNPs reduced mortality (11% vs. 79%; P<0.01) and improved neurological functions (median 9 vs. 3; modified Garcia score; P<0.01) post-SAH. Conclusions: Amicar-CeNPs, totally synthesized in aqueous phase, demonstrated very promising results against SAH via potent anti-oxidative, neuroprotective and anti-inflammatory activities. Given the obvious limitations of current therapies for SAH, Amicar-CeNPs are strongly required to be tested in SAH patients as an investigational new drug.
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