Abstract
Cerium oxide (CeO2) nanoparticles (CeNPs) are potent antioxidants that are being explored as potential therapies for diseases in which oxidative stress plays an important pathological role. However, both beneficial and toxic effects of CeNPs have been reported, and the method of synthesis as well as physico-chemical, biological, and environmental factors can impact the ultimate biological effects of CeNPs. In the present study, we explored the effect of different ratios of citric acid (CA) and EDTA (CA/EDTA), which are used as stabilizers during synthesis of CeNPs, on the antioxidant enzyme-mimetic and biological activity of the CeNPs. We separated the CeNPs into supernatant and pellet fractions and used commercially available enzymatic assays to measure the catalase-, superoxide dismutase (SOD)-, and oxidase-mimetic activity of each fraction. We tested the effects of these CeNPs in a mouse hippocampal brain slice model of ischemia to induce oxidative stress where the fluorescence indicator SYTOX green was used to assess cell death. Our results demonstrate that CeNPs stabilized with various ratios of CA/EDTA display different enzyme-mimetic activities. CeNPs with intermediate CA/EDTA stabilization ratios demonstrated greater neuroprotection in ischemic mouse brain slices, and the neuroprotective activity resides in the pellet fraction of the CeNPs. The neuroprotective effects of CeNPs stabilized with equal proportions of CA/EDTA (50/50) were also demonstrated in two other models of ischemia/reperfusion in mice and rats. Thus, CeNPs merit further development as a neuroprotective therapy for use in diseases associated with oxidative stress in the nervous system.
Highlights
Reactive oxygen species (ROS), including superoxide (O2 − ), hydrogen peroxide (H2 O2 ), peroxynitrite (ONOO- ), and hydroxyl radical (HO ), are byproducts of normal cellular metabolism; they play important roles in cellular physiology including signal transduction, adaptations to stress, and immune responses [1,2,3]
The physico-chemical variables for cerium oxide nanoparticles (CeNPs) stabilized with various ratios of citric acid (CA)/ethylenediaminetetraacetic acid (EDTA) fell within a narrow range, except for the particles at the extremes of either CA or EDTA (Table 1)
Those stabilized with higher proportions of CA had higher hydrodynamic diameters, and those stabilized with higher proportions of EDTA had less negative zeta potentials
Summary
Reactive oxygen species (ROS), including superoxide (O2 − ), hydrogen peroxide (H2 O2 ), peroxynitrite (ONOO- ), and hydroxyl radical (HO ), are byproducts of normal cellular metabolism; they play important roles in cellular physiology including signal transduction, adaptations to stress, and immune responses [1,2,3]. It is well known that oxidative stress plays a significant role in the pathology of multiple neurodegenerative conditions including stroke, amyotrophic lateral sclerosis (ALS), Parkinson’s. Edaravone is a spin trapping agent used as a drug for its antioxidant properties and was first approved for treatment of stroke in Japan. It has subsequently been approved for the treatment of early ALS in Japan and Korea, based on consistent (but not statistically significant) trends in multiple small Phase II and III studies, and later approved in the US [12,13,14]
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