Why is CPT interested in the impact of oxidative stress and inflammation in Parkinson's?

In recent years, there has been some considerable interest in the role of free-radical damage or oxidative stress and how the body responds to inflammation, in the Parkinsonian brain.  These 'stressor' factors create an environment in the brain which is not conducive to normal function and signs of oxidative damage have been shown to appear long before brain cells - neurons - actually degenerate in Parkinson's(PD):

  • Oxidative stress is essentially an imbalance between the production of highly chemically reactive substances in cells and the ability of the body to counteract or detoxify their harmful effects, resulting in cell damage or death.
  • Inflammation is the body's attempt at self-healing; the aim being to remove harmful substances, including damaged or degenerated cells and begin the healing process. When something harmful affects a part of the body, the biological response to try to remove it results in the signs and symptoms of inflammation.

Strong evidence now exists to support a role for abnormal mitochondrial activity and increased oxidative stress, in the cause, development and effects of PD. A complex interplay occurs between mitochondria and other cellular complexes that affects cell survival, as mitochondria not only have a key role in cell energy production, but they are also the main cellular source of free radicals.  

Mitochondrial dysfunction leads to increased oxidative stress. Oxidative damage to lipids, proteins and DNA as well as a decrease in the levels of the important intra-cellular antioxidant glutathione, has been detected in post mortem PD brain tissue. These findings provide a plausible link between oxidative damage and the formation of abnormal aggregates of protein that are characteristic of PD, as oxidative damage, it is thought, induces alpha-synuclein clumping and impairs the proper degradation of the proteins.

What are oxidative stressors?

Oxidative stressors are more commonly known as free radicals. These are highly reactive and potentially very damaging molecules which can be produced by normal chemical reactions in the body or absorbed from outside sources (such as cigarette smoke, pollutants or ingested toxins). Free radicals only last for very short periods of time in the body, but have the potential to do damage to cells during that time. Specifically, free radicals are molecules which have an odd number of electrons, either one too many or one too few. This causes the molecules to become unstable and very reactive, and in an attempt to address this electron imbalance, the free radicals then react with other neighbouring molecules. This process, known as oxidation, is thought to cause damage known as oxidative stress to tissues, cells and neurons. 

How does this process relate to Parkinson's?

Dopamine-producing cells in the substantia nigra region of the brain appear to be particularly at risk from free-radical production and damage and it is these dopamine cells which degenerate in Parkinson’s. There is also some evidence that oxidative stress may cause or contribute to Parkinson's itself (1): for example, people with PD have been found to have increased levels of iron in their brain (2), especially in the substantia nigra. Iron is a powerful agent of free-radical damage - it can intensify oxidative stress if it is in a free or unstable state. Normally, a cell will use a protein called ferritin to surround the iron (a process known as iron chelation), this prevents the iron from stimulating oxidative stress, but levels of ferritin are also found to be lower in the brains of people with PD. Antioxidants (also known as free-radical hunters) maintain some control by offering themselves as easy targets to 'mop up' the free radicals. Antioxidants are chemicals produced by the body or absorbed from the diet which neutralise the effects of free radicals. Antioxidants stabilise lone free-radical molecules and make them stable enough to be transported to an enzyme, which combines two stabilised free radicals together to neutralise both. The brain contains multiple antioxidant defences. However, the level of one of the body's own powerful intra-cellular antioxidants, glutathione, has been shown to be reduced in the brains of people with Parkinson’s (3).

How is CPT shaping its research around oxidation and inflammation?

Substantial evidence from brain tissue, cell growth and animal models of PD along with the analysis of human genetics support the involvement of oxidative stress and mitochondrial dysfunction in Parkinson's progression and development. Mitochondrial dysfunction due to oxidative stress, mitochondrial DNA mutations during replication, altered mitochondrial structure and the interaction of pathogenic proteins such as a-synuclein with mitochondria all result in dopaminergic neurodegeneration. Thus, therapeutic approaches targeting mitochondrial dysfunction and related oxidative stress may hold significant potential in the treatment of PD.

A number of antioxidant compounds have received specific attention from researchers and CPT is funding some promising studies here. Several have shown promise as neuroprotective agents:

The Simvastatin trial

The Deferiprone trial

The NAC trial

See also Dr Kambiz Alavian's research (Imperial College, London) - 'Identification of new drugs to improve neuronal energy production for treatment of PD' in our 'Preclinical projects' section. 


(1) 'Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis' - Claire Henchcliffe and M Flint Beal (Nature Clinical Practice Neurology (2008) 4, 600-609)

(1) 'Role of Oxidative Stress in Parkinson's Disease' - Onyou Hwang (Published online 2013 Mar 31)

(2) 'Regulation of ATP13A2 via PHD2-HIF1 a-Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease' - 
Subramanian Rajagopalan, Anand Rane, Shankar J. Chinta, and Julie K. Andersen (The Journal of Neuroscience- 27 January 2016)

(3) 'Glutathione, iron and Parkinson’s disease' - Srinivas Bharath, Michael Hsu, Deepinder Kaur, Subramanian Rajagopalan, Julie K Andersen (Biochemical Pharmacology Volume 64, Issues 5–6, September 2002)