Ceria Nanoparticles Synthesized With Aminocaproic Acid for the Treatment of Subarachnoid Hemorrhage

Abstract

Background and Purpose— Despite early aneurysm repair and aggressive management for complications, subarachnoid hemorrhage (SAH) results in at least 25% mortality rate and 50% persistent neurological deficit. We investigated whether ceria nanoparticles which have potent antioxidative activities can protect against subarachnoid hemorrhage via attenuating fatal brain injuries. Methods— Uniform, 3 nm, water-dispersed ceria nanoparticles were prepared from short sol-gel reaction of cerium (III) ions with aminocaproic acid in aqueous phase. SAH was induced by endovascular perforation of middle cerebral artery of rats. A single dose of ceria nanoparticles (0.5 mg Ce/kg) or saline control was randomly administered intravenously at an hour post-SAH. Neuronal death, macrophage infiltration, SAH grade, and brain edema were evaluated at 72 hours. Mortality and neurological function were assessed for 14 days. Results— The obtained ceria nanoparticles with high Ce 3+ to Ce 4+ ratio demonstrated potent antioxidative, cytoprotective, and anti-inflammatory activities in vitro. In rodent SAH models, the severity of hemorrhage was comparable between the ceria nanoparticles- and saline-treated groups. However, ceria nanoparticles significantly reduced neuronal death, macrophage infiltration, and brain edema after SAH. Ceria nanoparticles successfully improved survival rates (88.2% in the ceria nanoparticles group versus 21.1% in the control group; P <0.001) and neurological outcomes (modified Garcia score: 12.1±0.5 in the ceria nanoparticles group versus 4.4±0.5 in the control group; P <0.001) of the animals with SAH. Conclusions— Ceria nanoparticles, totally synthesized in aqueous phase using aminocaproic acid, demonstrated promising results against SAH via potent antioxidative, neuroprotective and anti-inflammatory activities. Given the obvious limitations of current therapies for SAH, ceria nanoparticles can be a potential therapeutic agent which might result in a paradigm shift in SAH treatment.

Ceria Nanoparticles Ameliorate White Matter Injury After Intracerebral Hemorrhage: Microglia-astrocyte Involvement in Remyelination

“…CeNPs have both SOD mimetic (eradicating superoxide anions and hydroxyl radicals) and catalase mimetic (eradicating hydrogen peroxide), which enable it to eradicate ROS repetitively. Previous studies demonstrated that CeNPs treatment could protect against BBB disruption and neuronal death in several CNS disorders (23,37). However, whether CeNPs treatment shows similar bene ts in WMI is still contentious.…”

Nanoparticle-Based Technology Approaches to the Management of Neurological Disorders

“…There have also been various studies conducted on NPs for application in haemorrhagic stroke. Jeong et al studied CeO 2 NPs and their ROS scavenging abilities in the context of subarachnoid haemorrhage, the most devastating type of stroke, which is known to have a flux of ROS produced in the early progression of the disease [ 170 ]. The same investigators synthesized CeO 2 NPs using aminocaproic acid as a surface modifier, and conducted a randomized trial in an animal model to determine whether free radical scavenging therapy using the synthesized NPs, reduced mortality and improved neurological outcomes.…”

“…The same investigators synthesized CeO 2 NPs using aminocaproic acid as a surface modifier, and conducted a randomized trial in an animal model to determine whether free radical scavenging therapy using the synthesized NPs, reduced mortality and improved neurological outcomes. They reported that the NPs displayed a strong capability to protect the brain against subarachnoid haemorrhage, via prominent and versatile ROS scavenging effects, suggesting the potential for future clinical applications, warranting further preclinical testing such as profiling of pharmacokinetics and toxicity effects [ 170 ]. You et al investigated loading NPs with astaxanthin (ATX), a carotenoid with strong antioxidant and inflammatory properties [ 171 ].…”

<p>Nanocarriers for Stroke Therapy: Advances and Obstacles in Translating Animal Studies</p>

“…102 In a rat hemorrhagic stroke model, IV injection of CeO 2 nanoparticles had reduced neuronal death, immune cell infiltration and cerebral edema. 103 These do not however exemplify DDS technology. Therefore, in a recent study, CeO 2 nanoparticles were loaded with edaravone and conjugated with angiopep-2 and PEG.…”