University of Central Florida Foundation, Inc. (Orlando, FL)

A method for treating patients with elevated levels of peroxynitrite includes administering an amount that is therapeutically effective of cerium oxide nanoparticles the subject. The cerium oxide nanoparticles reduce the peroxynitrite levels in the patient.

The term neurodegeneration refers to the impairment or loss of function, structure, or the function of neurons. This also includes the dismemberment and death of neurons. Neurodegeneration results from various different causes including genetic mutation,mitochondrial dysfunction, and the inability to handle increasing levels of oxidative or nitrosative stress can also lead to the progression of neurodegeneration (67). Evidence from numerous in vitro and in vivo studies suggests that there is acommonality of the causes that lead to the development of a variety of neurodegenerative diseases that are a result of aging. A few of these neurodegenerative disorders include Huntington’s disease, Amyotrophic Lateral Sclerosis (ALS) and one of the most frequent of the neurodegenerative disorders is Alzheimer’s disease (AD). AD is a severe and progressive disease that could cause irreversible damage to patients, caregivers, society, and even the environment. There is increasing evidence in AD and other neurodegenerative diseases which suggests a link between both nitrosative and oxidative stress. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), create the nitrosative stress within cells.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) occur during normal metabolism . However, an imbalance may be caused by the increase in the production of free radicals or from the inability of antioxidants or antioxidant enzymes to effectively scavenge damaging molecules. The imbalance has been shown as a contributing factor in AD (69). Several studies provide clear evidence that RNS, in particular peroxynitrite (ONOO.sup.-) formation, contributes to the pathologies of chronicneurodegenerative diseases such as AD, Parkinson’s disease, multiple sclerosis, and Amyotrophic lateral sclerosis (4). Peroxynitrite is formed from the reaction of nitric oxide radical (NO) with superoxide (O2.sup .-). The most important cause of neurotoxic effects that ONOO.sup. promoting neurotoxic effects are mitochondrial injuries (5 6, 7). The increase in protein nitration within neurons may indicate extensive ONOO.sup.-mediated brain damage.

The administration of antioxidants and antioxidant enzymes for the treatment of illnesses caused by increased ROS and RNS in human clinical trials has so far been less than satisfactory due to issues with bioavailability as well as stability following administration.

This demand was satisfied with synthetic catalytic scavengers that scavenge ROS and RNS. They have been tested in various models. Copious metalloporphyrins have been synthesized to show high reactivity to, O.sub.2.sup.-, H.sub.2O.sub.2 NO andONOO.sup.(14-17). (14-17). Most studies affirm metalloporphyrins are effective tools in study and understanding the roles that ROS and RNS may play in diseases However, their potential toxicity caused by metals has frequently come into question for their use in humans.

Neurons have a high energy requirement and contains many hundred mitochondria in each cell. This means they are more prone to ROS and NNS. Mitochondria are a primary site of the intercellular formation of ONOO.sup.- (12) and mitochondrialdysfunction has been shown to contribute to disease or neuronal death (13). The ability to remove ONOO.sup.- – is crucial for therapeutic intercession in degenerative diseases that are characterized by the overproduction or unbalanced production of O.sub.2.sup.- and NOand thus, ONOO.sup.-.

The mitochondria are constantly divided and fusion in order to continue to produce energy. Evidence suggests that an imbalance in mitochondrial division and fusion is the cause in AD (78). Mitochondrial division and fusion is regulatedby large GTPases of the dynamin family. For mitochondrial division, Dynamin-related Protein 1 (DRP1) must be expressed. The presence of the GTPase defective DRP1.sup.K38A mutant guards against excess NO, NMDA, or A.beta. (5). It is unclear what causes mitochondrial break-up caused by NO. A recent report suggested that S-nitrosylation of DRP1 at cysteine 644 increases DRP1 activity and is the cause for theperoxynitrite-induced mitochondrial fragmentation in AD (85, 50). The work is still controversial and suggests that other pathways may be involved (85,86). DRP1 Serine 616 (S616) the phosphorylation process is fast under nitrosative stress, and promotes its translocation to organelle and mitochondrial division (86-87). DRP1 5616 phosphorylation in mitotic cells is controlled by Cdk1/cyclinB1, a protein that is synchronized with the division of mitochondria and cell division (88-89). It is interesting to note that p-DRP1 S616 levels are markedly increased in brains of individuals with AD and suggests that this process could contribute to the alteration in mitochondrial morphology as well as energy metabolism in AD (86, and 88). While the kinase that causes DRP1 5616 hyperphosphorylation is unknown Cdk5/p25 may be a possible kinase that mediates the process (7,90). Notably, aberrant Cdk5/p25 signaling causes tau hyperphosphorylation in postmitotic neurons and is involved in A.beta.-mediated neurodegeneration (88, 90-93).

The brain’s physical changes are just a few of the effects that Alzheimer disease or other neurodegenerative disorders have in the brain. One example of these changes is the formation of plaque-like and neurofibrillary tangles. Microglia activation due to illness, injury or aging, among other reasons, can trigger events that are classified as an inflammation process. These processes are first controlled through the proinflammatory cytokine Interleukin 1. This is overexpressed by activated microglia. Through different channels, interleukin 1 triggers neuronal death, which activates the microglia. The microglia in turn releases more interleukin 1, in self-sustaining, self-amplifying way. Over time, this slow, smolderinginflammation in the brain destroys sufficient neurons to cause the clinical signs of Alzheimer disease.

Cerium oxide nanoparticles (CeO.sub.2 NPs) have been recently demonstrated to efficiently scavenge reactive oxygen species within a variety of model systems. The mechanism by the nanoparticles of cerium oxide activate these redox reactions is tied to the surface chemistry as well as the the redox state of cerium, and is dependent on the preparation. Peroxynitrite is a neurotoxic nitrogen compound which plays a role in the development of numerous neurodegenerative disorders. Scavengingperoxynitrite provides beneficial therapeutic effects in both neurodegenerative diseases and in many diseases where inflammation in the brain is a critical contributing factor. Conventional antioxidants primarily scavenge only reactive oxygen species and are not effective against nitrogen species that are reactive. Cerium oxide, which is a rare-earth oxide nanomaterial, is utilized to eliminate peroxynitrite in vitro. This newly discovered catalytic property of cerium oxide offers protection in aprimary neuronal cell model. Cerium oxide nanoparticles are absorbed by neurons and are accumulated within mitochondria, which is the main source of reactive nitrogen species within neurons. The Cerium oxide nanoparticles against endogenousnitric dioxide or endogenous peroxynitrite. This is possible via mitochondrial toxins or excess glutamate or A.beta.eta.peptide. The rare earth nanoparticles offer protection against neurodegeneration. They also have lower levels protein tyrosine as well as fewer reactive nitrogenspecies. A new discovery that cerium oxide nanoparticles are utilized to reduce the levels of peroxynitrite to stop neurodegeneration was discovered.

Cerium oxide nanoparticles exhibit low toxicity (18, 19). It was discovered that their ability to change between the 3.sup.+ and 4.sup.+ state of oxidation gives CeO.sub.2 nanoparticles an unique antioxidant role.

CeO.sub.2 NPs have been shown to protect several cell types and animal models against ROS mediated illnesses (20). Nanoparticles generally exhibit unique features on their surfaces that may alter their chemistry as well as their interaction with biological systems. CeO.sub.2NPs possess a crystal structure and are made up of reactive sites. CeO.sub.2NPs can interchange between the 3.sup.+ and 4.sup.+ states of the oxidation process (21). It’s difficult to control the relative levels of vacancies and reactive sites, but CeO.sub.2 has been able to create NPs that are able to switch between the3.sup.+ and 4.sup.+ state of oxidation (21). It should be noted that CeO.sub.2 NPNs with lower3.sup.+/4.sup.+ ratio exhibit higher catalase mimetic activity (23). CeO.sub.2NPs have been demonstrated to be neuroprotective in variety of neuronal culture models (24-25). Recent studies in vivo confirm the antioxidant properties of CeO.sub.2 NPs, which have low toxicity to the brain in rodent models (27 28). The capability of CeO.sub.2 NPs to react with ONOO.sup.In vitro as well as an evaluation of the neuroprotective properties of CeO.sub.2 NPs during the nitrosative stress process is described herein. Also provided hereinis a demonstration that certain CeO.sub.2 NPs protect against A.beta.-induced DRP1 5616 hyperphosphorylation, mitochondrial fragmentation and neuronal cell death

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