Parkinson’s and oxidative stress

In recent years, there has been considerable interest in the role of oxidative stress in the brain cells of people with Parkinson’s. This stress creates an environment which is not conducive to normal function, and signs of oxidative stress can appear long before nerve cell (neuron) loss begins in Parkinson’s.

Oxidative stress is defined as a chemical imbalance within our cells between toxic molecules called reactive oxygen species (ROS) and the ability of cells to detoxify them. ROS are a natural by-product of cellular energy production, created from a series of reactions in the mitochondria. In the neurons of people with Parkinson’s, however, issues with mitochondria are common, leading to build-ups of these compounds. Unable to detoxify them, ROS can react with other cell structures, leading to damage and eventually cell death.

Strong evidence now exists to support abnormal mitochondrial activity and increased oxidative stress, in the cause, development and effects of Parkinson’s. Mitochondria are small structures inside cells that are responsible for energy production. A complex relationship occurs between mitochondria and other cellular processes that affect cell survival, as mitochondria are also the main source of waste products in cells. There is also a plausible link between oxidative damage and the formation of abnormal clumps of protein that are characteristic of Parkinson’s – oxidative damage is believed to play a part in the formation of misfolded alpha-synuclein and prevention of the proper breakdown of this clumped toxic protein.

What are reactive oxygen species (ROS)?

ROS are a special type of molecule called a “free radical”. Free radicals are highly reactive, unstable molecules that, if left untreated, can react and damage parts of the cell. Oxidative stress is thought to interact and play a role in other aspects of Parkinson’s biology as well. There is some evidence to suggest that oxidative stress may contribute to, or even accelerate, the build-up of the protein alpha-synuclein in neurons. Accumulation of dysfunctional copies of alpha-synuclein are considered a hallmark of Parkinson’s and thought to be a driver of cell loss.

Furthermore, higher alpha-synuclein levels are associated with increased ROS production, creating a toxic feedback loop between them.

Why target iron?

Studies have indicated that iron levels are higher in the brains of people with Parkinson’s, leading to questions about whether this could be affecting progression. Researchers have proposed this may be contributing to oxidative stress since reactions with iron ions – reactive, charged molecules – can produce excess ROS. Additionally, high iron levels may trigger a special cell death pathway called ferroptosis, leading to neuron loss. For these reasons, researchers are interested in whether therapies able to lower iron levels could protect neurons in Parkinson’s.

Several iron chelators – therapies that remove excess iron from the body – have been examined both in the laboratory and in clinical trials for Parkinson’s. The FAIRPARK-II study was a phase 2 clinical trial which looked to see whether deferiprone could slow Parkinson’s progression in 372 people with Parkinson’s over the course of nine months. Although deferiprone did reduce iron levels, clinical measurements indicated a worsening of motor symptoms in the participants taking deferiprone.

Given that the findings from FAIRPARK-II do not confirm findings from previous studies, further research questions need to be investigated. These include determining the ideal time to begin treatment with iron chelators, as well as assessing other approaches to reduce iron in Parkinson’s that may have fewer side-effects.

It has been suggested that taking dopamine replacement therapies could counteract the effect of deferiprone on dopamine synthesis and this is something that is being investigated further. Cure Parkinson’s is now funding the development of next generation iron targeting agents, and the learnings of the FAIRPARK-II study will aid the future clinical development of these drugs.