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WIREs Nanomed Nanobiotechnol
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Cerium oxide nanoparticles in neuroprotection and considerations for efficacy and safety

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Cerium oxide nanoparticles have widespread use in the materials industry, and have recently come into consideration for biomedical use due to their potent regenerative antioxidant properties. Given that the brain is one of the most highly oxidative organs in the body, it is subject to some of the greatest levels of oxidative stress, particularly in neurodegenerative disease. Therefore, cerium oxide nanoparticles are currently being investigated for efficacy in several neurodegenerative disorders and have shown promising levels of neuroprotection. This review discusses the basis for cerium oxide nanoparticle use in neurodegenerative disease and its hypothesized mechanism of action. The review focuses on an up‐to‐date summary of in vivo work with cerium oxide nanoparticles in animal models of neurodegenerative disease. Additionally, we examine the current state of information regarding biodistribution, toxicity, and safety for cerium oxide nanoparticles at the in vivo level. Finally, we discuss future directions that are necessary if this nanopharmaceutical is to move up from the bench to the bedside. WIREs Nanomed Nanobiotechnol 2017, 9:e1444. doi: 10.1002/wnan.1444 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Hypothesized mechanism of action of cerium oxide nanoparticles (CeONPs). In a given CeONP, the cerium atom exists in the 3+ and 4+ valence states, bound to oxygen and containing oxygen vacancies (Ov). When exposed to a superoxide radical, it exhibits superoxide dismutase (SOD) mimetic activity, and Ce3+ is converted to Ce4+, with a corresponding change in oxygen vacancies. There is also likely a contribution to this reaction from the hydration shell around the CeONP. Superoxide is converted to H2O2. Via a catalase‐mimetic activity involving Ce4+, H2O2 is converted to O2 + 4H+, and cerium valence to +3 (with corresponding changes in oxygen vacancies), regenerating the origin CeONP state. Again, there is a likely contribution from ions present in the water hydration shell. In the biological milieu, this action exists in a continuous cycle, depending on the ionic species exposed to the CeONPs, the hydration shell, oxygen partial pressure, and any surrounding ionic species. Although we utilized superoxide and H2O2 as examples, radicals scavenged could be any number of biologically relevant free radicals.
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Biodistribution of cerium oxide nanoparticles (CeONPs) to selected organs 2 days (a) and 6 months (b) after intravenous injection. Rats were treated with the indicated doses of CeONPs as described in the text. Two days or 6 months after treatment, animals were killed and tissues collected for ICP‐MS analysis of cerium. Results represent mean ± SE for six animals.*p < 0.01 compared to saline control.
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Pretreatment with cerium oxide nanoparticles (CeONPs) improve latency to goal in the Morris water maze and beam balance performance after moderate lateral fluid percussion brain injury. Male Long‐Evans rats were pretreated with 0.14 mg/kg CeONPs followed by a moderate lateral fluid percussion brain injury 3 days later (six animals per group). Sham animals received CeONPs and the surgery for lateral fluid percussion brain injury, without delivery of the brain injury. On the indicated day postinjury, rats were tested for latency to platform in the Morris water maze task (a) and for beam balance latency to fall (b). Note the significant improvement, to near‐sham levels, with CeONP pretreatment. Results represent mean ± SE for six animals per group. *Significant from sham, P < 0.01; **significant from sham and injury + CeONP; #Significant from injury + vehicle and sham.
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Cerium oxide nanoparticle (CeONP) preserves TH+ neurons in the substantia nigra of MPTP‐challenged mice. Mice (C57Bl/6) were pretreated with the indicated dose of 10‐nm CeONP in saline citrate, followed by MPTP challenge 5 days later (six animals per group). Animals were killed 7 days after MPTP administration, brains were perfusion fixed, and stained for tyrosine hydroxylase (TH+, brown), a marker of dopaminergic neurons. Nuclei are counterstained with Nissl (blue). Note the almost complete destruction of dopaminergic neurons by MPTP (upper right panel), which was abrogated in CeONP‐treated mice (lower two panels).
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