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Cerium Oxide Nanoparticles Show Promise in Animal Models of Parkinson's and Other Neurologic Diseases



ARTICLE IN BRIEF

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ELECTRON MICROGRAPH of cerium oxide nanoparticles.

Three studies presented at the Society for Neuroscience annual meeting in November suggest that cerium oxide nanoparticles hold promise as a disease-modifying therapy for Parkinson's and as a treatment for stroke and mild traumatic brain injury.

WASHINGTON, DC—An in-dustrial additive for diesel fuels holds promise as a disease-modifying therapy for Parkinson's and as a treatment for stroke and mild traumatic brain injury, according to studies presented here at the annual meeting of the Society for Neuroscience in November.

The biological benefit appears to derive from the same quality that makes the additive, cerium oxide nanoparticles, useful in diesel fuel: it has a unique ability to improve the functioning of the electron transport chain, which is fundamental to the production of energy, whether in truck engines or in mitochondria. In so doing, the nanoceria, as they are also known, appear to function as a self-regenerating antioxidant, mopping up free radicals for months after a single treatment.

The investigators tested this approach in a mouse model of Parkinson's disease. Twelve hours after a series of four injections with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a single IV infusion of cerium oxide nanoparticles preserved striatal dopamine by approximately 50 percent and dopaminergic neurons in the substantia nigra by 84 to 87 percent compared with controls. When animals not treated with MPTP were given the cerium oxide nanoparticles alone, their levels of tyrosine hydroxylase-positive neurons in the substantia nigra increased. This suggests that the treatment might halt or slow disease progression and, by promoting neuron growth in the substantia nigra, potentially reverse Parkinson's disease pathology.

“MPTP is a pretty extreme insult,” Walter J. Koroshetz, MD, FAAN, acting director of the National Institute of Neurological Disorders and Stroke, told Neurology Today. “The fact that [cerium oxide nanoparticles] have this fairly tremendous effect is interesting. Reactive oxygen species (ROS) seem to be involved in a whole lot of things that kill brain cells, including stroke and traumatic brain injury.”

He noted, however, that the MPTP model of Parkinson's, which depends on the production of ROS, has given way to the alpha-synuclein and other genetic models, which are not as strongly ROS-driven. “It would be interesting to see what these nanoparticles do in these other models,” he said.

The presence of oxidative stress in the striatum and substantia nigra of Parkinson's brains has long been established, said Beverly A. Rzigalinski, PhD, a professor of pharmacology at the Edward Via College of Osteopathic Medicine in Blacksburg, VA, and the senior author of the study.

“These particles are smaller than a virus, so they get into the brain and stay there,” Dr. Rzigalinski said. “They're like a factory for dismantling free radicals.”

With funding from the Michael J. Fox Foundation, Dr. Rzigalinski's group has now completed toxicology studies in mice aimed at paving the way for an investigational new drug application with the FDA. “We're hoping to generate interest from pharmaceutical companies to move this up to the next stage, to eventually get it into clinical trials,” she said.

In a second study presented at the Society for Neuroscience meeting by Dr. Rzigalinski's group, cerium oxide nanoparticles significantly improved both short-term memory and anxiety-like behavior compared with untreated animals (p<0.04) in a rodent model of lateral fluid percussion injury. In the group's third study, in which Drosophila (fruit flies) were kept in anoxic conditions for 2.5 hours as a model of stroke, survival and motor function significantly improved.

EXPERTS COMMENT

Studies in mice and fruit flies don't always translate to the clinic, several researchers who were not involved in the studies told Neurology Today. But they noted that the findings build on a growing body of preclinical work demonstrating the benefits of cerium oxide nanoparticles in multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

“The idea that oxidative stress plays a role in neurodegenerative diseases is not novel,” said James C. Leiter, MD, a professor of physiology, neurobiology and medicine at the Geisel School of Medicine at Dartmouth College, who was not involved with the study.

Dr. Leiter, who has a series of preclinical studies of nanoceria in both MS and ALS, added, “I do think the oxidative stress hypothesis of neurodegeneration was correct, but really effective antioxidants weren't previously available to adequately test the hypothesis. Cerium oxide nanoparticles look like they will be an effective antioxidant.”

Because they are just 1.8 to 2.5 nanometers in width, the nanoceria are small enough to cross the blood-brain barrier with ease, and have been shown to continue functioning for up to six months, said Joseph S. Erlichman, PhD, a professor of biology at St. Lawrence University and a senior collaborator of Dr. Leiter's.

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DR. BEVERLY A. RZIGALINSKI: “Were hoping to generate interest from pharmaceutical companies to move this up to the next stage, to eventually get it into clinical trials.”

Not only do the particles strip free radicals of their spare electron, Dr. Erlichman said, they also then donate that spare electron to hydrogen peroxide in a seemingly perpetual shuffling process.

Along with a large team of other researchers, Dr. Erlichman and Dr. Leiter have coauthored two papers on the potential uses of cerium oxide nanoparticles — one in a mouse hippocampal brain slice model of ischemia, and another in a mouse model of free radical-mediated autoimmune degeneration.

Dr. Leiter said he agrees with Dr. Koroshetz that the Parkinson's findings should be replicated in a study that does not use MPTP. He also emphasized that cerium oxide nanoparticles cannot yet be considered a therapy. “A lot of work has to be done to show it's both safe and effective in humans,” he said. “This is an incredibly exciting beginning, but it's still just a beginning.”

Dr. Rzigalinski began her studies of the substance in 2002, when an engineer at the University of Central Florida, where she worked at the time, approached her with the suggestion that she try them out.

“I gave the project to an undergraduate,” she recalled. “We were culturing mixed astrocytes as an in vitro model of head injury. I figured that adding the nanoparticles would be like dropping rocks on the cells, and they would all die. A month and a half later, I noticed my student's cells were still in the incubator. I asked him why. ‘Well, Dr. Z,’ he said, ‘the controls are all dead, but the ones I treated with the nanoparticles are still alive.’ We ended up keeping that neuronal cell culture alive for six months.”

Twelve years later, research into the diesel fuel additive shows no sign of running out of gas.

EXPERTS: ON CERIUM OXIDE AS A DISEASE-MODIFYING THERAPY FOR PARKINSON'S

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DR. WALTER J. KOROSHETZ noted that the MPTP model of Parkinsons, which depends on the production of reactive oxygen species (ROS), has given way to the alpha-synuclein and other genetic models, which are not as strongly ROS-driven. “It would be interesting to see what these nanoparticles do in these other models,” he said.

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DR. JAMES C. LEITER: “I do think the oxidative stress hypothesis of neurodegeneration was correct, but really effective antioxidants werent previously available to adequately test the hypothesis. Cerium oxide nanoparticles look like they will be an effective antioxidant.”

LINK UP FOR MORE INFORMATION:


•. Society for Neuroscience annual meeting abstract: Cerium oxide nanoparticles as disease-modifying therapy for Parkinson's disease: bit.ly/ceriumoxide-pd
    •. Society for Neuroscience annual meeting abstract: Cerium oxide nanoparticles improve functional outcomes following mild traumatic brain injury: bit.ly/ceriumoxide-tbi
      •. Society for Neuroscience annual meeting abstract: Cerium oxide nanoparticles improve survival and motor function in a Drosophila model of stroke. bit.ly/ceriumoxide-stroke
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        •. Kolli MB, Manne ND, Para R., et al. Cerium oxide nanoparticles attenuate monocrotaline induced right ventricular hypertrophy following pulmonary arterial hypertension. Biomaterials 2014;35(37):9951–9962.
        •. Gao Y, Chen K, Ma JL, et al. Cerium oxide nanoparticles in cancer. Onco Targets Ther 2014;7:835–840.