Encapsulating the antioxidant small molecule ellagic acid into a nanoparticle that also has some antioxidant properties may be a promising approach to treat neurodegenerative conditions, such as Parkinson’s disease, in which oxidative stress plays a critical role, a study suggests.
In addition to reducing reactive oxygen species (ROS) — which when not cleared properly results in oxidative stress — and ROS-induced cell death better than any compound used alone, the approach also mitigated the toxicity of ellagic acid to cells, which has largely prevented its clinical development to date.
The study, “Chitosan-Ellagic acid Nanohybrid for mitigating rotenone-induced oxidative stress,” was published in the journal ACS Applied Materials and Interfaces.
Oxidative stress, or the imbalance between the production and clearance of toxic reactive species that are harmful to cells, such as ROS, is thought to play a key role in neurodegenerative diseases like Parkinson’s.
These toxic substances are increased as a result of deficient mitochondria (the cell’s powerhouses) and are thought to damage dopamine-producing neurons in Parkinson’s, eventually causing them to die.
Antioxidant small molecules found in nature, such as ellagic acid, are seen as a promising way to reduce the oxidative stress and nerve cell damage observed in patients, but because most of these molecules are not very soluble, patients would need to receive high doses, which can be toxic.
Researchers at The University of Texas at El Paso investigated whether encapsulating ellagic acid into a nanoparticle could reduce its toxicity while retaining its antioxidant properties. But instead of using a synthetic compound to create the particle, the team turned to chitosan, a biodegradable sugar molecule found in the hard outer skeleton of shellfish.
Notably, chitosan also has some antioxidant properties, which could improve the therapeutic effects of this approach.
After designing and developing their antioxidant nanoparticle, researchers tested their approach in cells cultured with rotenone, a pesticide known to inhibit the function of mitochondria and to induce oxidative stress. Rotenone often is used in animals to induce Parkinson’s-like symptoms.
Overall, the team found that the encapsulated formulation lowered the levels of toxic reactive species more efficiently, and prevented rotenone-induced neuronal cell death more than the nanoparticles alone or ellagic acid alone.
Also, while ellagic acid killed about 15% of cells in culture, nearly no cells died when cultured with the encapsulated formulation of this antioxidant.
“The results suggest that EA [ellagic acid] entrapped in chitosan-based nanoparticle system can serve as a better protecting agent against rotenone insult than EA alone,” the researchers wrote.
Importantly, the researchers noted that an ideal treatment should be able to release the active component in bursts, helping treat acute episodes of oxidative stress, and in a sustained manner given that reactive oxygen species are cleared up as they appear.
The team found that its nanoparticle system was able to do just that, releasing about 50% of ellagic acid in the first couple of hours, and then slowly releasing the remaining ellagic acid in the next 10 hours.
“This work creates a new type of bio-friendly drug-delivery vehicle made of recyclable materials,” Mahesh Narayan, PhD, who co-led the study, said in a press release. “The other special feature of this vehicle is that it can deliver the drug via two mechanisms: one rapid and the other a slow-release.”
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