Why is The Cure Parkinson's Trust(CPT) investigating whether NAC might be a beneficial treatment in Parkinson’s(PD)?

Acetylcysteine, also known as N-acetylcysteine or NAC is a medication currently used to treat paracetamol overdose and mucous build-up in conditions such as cystic fibrosis.

Parkinson’s disease may result from several unrelated genetic mutations, environmental toxins and/or from as yet unidentified interactions between genetic and environmental factors. Several lines of evidence however indicate that depletion of glutathione (GSH) - a naturally occuring potent intracellular antioxidant - is a contributory factor in the development of PD. The normalisation of GSH levels may prevent or relieve both oxidative stress* and cell death. GSH works by binding with toxic free-radicals in the body which are then broken down and excreted.  It is believed that NAC restores levels of GSH in neurons by functioning as a cell-permeable source of cysteine (which is the prerequisite for GSH synthesis). GSH itself cannot be given directly because it rapidly breaks down in the body and insufficient amounts can cross the blood brain barrier; also neurons cannot absorb it in its natural form.

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.

Why do researchers think this drug is a potential treatment to slow, stop or reverse Parkinson’s?

It has been recognised that reduced neuronal glutathione (GSH) is an early and characteristic hallmark of Parkinson’s and that reductions in glutathione lead to death of dopaminergic and other neurons. NAC can replenish levels of the intracellular antioxidant glutathione (GSH) and normalisation of GSH levels may prevent or ameliorate oxidative stress and cell death. In addition, NAC may also have a direct role in neuroprotection as a scavenger of oxygen radicals, as a modulator of the immune system and in mitochondrial processes.  Several animal models of PD have shown that NAC ameliorates dopaminergic neuronal loss.   

What do we hope will be the result of this important trial? 

The use of N-acetyl cysteine (NAC) has been proposed as a disease modifying therapy.  NAC is already approved for use in both short term and long-term conditions and given the known associations between GSH and PD pathogenesis, it is a promising neuroprotective therapy in PD. NAC is also available as a non-regulated nutritional supplement.  Ultimately its beneficial effect can only be demonstrated in a large scale clinical efficacy trial but at present more information is needed. There is a lack of information about the penetrance of NAC into the brain and the doses required to influence neuronal glutathione levels in humans. This trial will allow us to gather essential evidence about aspects such as the optimum dose levels and will help us to decide whether NAC has beneficial disease-modifying effects in people with PD and ultimately whether the safety, tolerability and natural effects of the use of NAC support its widespread use in PD. Click here for more information about NAC use in Parkinson's.

Who will be involved in this study?

Our ideal study design will be based on a multicentre, randomised, double blind, placebo controlled dose ranging clinical trial of NAC versus placebo for PD patients on stable dopaminergic therapy (early to moderate stage PD). Subjects will be randomized in a 2:1 ratio to active drug or placebo.  Following enrolment, all patients (approx. 60) will be treated with NAC or placebo for 6 months in order to measure safety, tolerability and changes in secondary outcome measures.  

Initially, plans were to conduct this study in the US but obtaining funding for a compound of this type i.e. with little or no commercial potential is challenging and study costs being considerably lower in the UK, CPT are now pursuing plans to fund and run the trial in the UK although still with the invaluable input of Prof Carlie Tanner.

Funding is still needed for this trial.