One of the major genetic risk factors believed to contribute to the development of Parkinson’s disease (PD) is having a mutation in the gene called GBA1 (glucocerebrosidase). Unable to do its job correctly, this damaged gene leads to the build-up of unhealthy, misfolded clumps of alpha-synuclein in the brain. These clumps, called Lewy bodies, impact dopamine production and are the hallmark of PD. What if there was a way to prevent the build-up of Lewy bodies in the first place?
A 2020 study published in JAMA Neurology, titled, “Ambroxol for the Treatment of Patients with Parkinson Disease with and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial” (Mullin et al., 2020), investigated whether an over-the-counter cough syrup, called Ambroxol, may be the key. The cough syrup, specifically, an expectorant, is used to break up phlegm.
Shown in previous studies to improve GBA1 function in neurons, this 2a study (known as a proof-of-concept study) set to find out if Ambroxol could cross the blood/brain barrier, and function as a molecular chaperone (in other words, physically help the GBA1 protein function properly).
This 186-day clinical trial of 17 people with PD ― with and without the GBA1 mutation ― involved participants taking progressively increasing doses of Ambroxol in the form of an oral tablet. Baseline measurements included physical and neurological examination, an electrocardiogram, blood sampling and spinal fluid examination obtained by lumbar puncture. Three additional in-person clinical visits were held on day 11, day 93, and day 186. Of note, at baseline, Ambroxol was undetectable in both the blood serum and spinal fluid. All study participants continued their normal L-dopa therapy throughout the trial.
In study participants both with and without the gene mutation:
- Ambroxol successfully crossed the blood-brain barrier.
- Ambroxol was safe and well-tolerated at the administered dose.
- Ambroxol successfully bound to the mutated genes’ protein, which physically helped the protein function properly.
- Healthy levels of alpha-synuclein increased in the spinal fluid.
What Does This Mean?
This study showed that Ambroxol is safe to use as a treatment in people with Parkinson’s. Ambroxol may slow the progression of Parkinson’s disease. How? Taking Ambroxol as a medication can prevent the negative effects of the GBA mutation ― including possibly reducing the formation Lewy bodies at the source. Ambroxol shows promise, and warrants further investigation ― including conducting larger, placebo-controlled trials.
Of note, while Ambroxol has been used as a safe and effective over the counter expectorant for adults and children in more than 50 countries for 30-plus years, the administered dose in this trial was approximately 10 times the specified dosage. Additionally, Ambroxol is currently not approved for prescription or over the counter use by the U.S. Food and Drug Administration (FDA) for any indication, at this time.
The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about the Parkinson’s and the GBA mutation in the below Parkinson’s Foundation resources or by calling our free Helpline at 1-800-4PD-INFO (473-4636).
- GBA Mutation May Lead to Novel Therapeutics
- Genetic Differences Linked to Faster Rate of Parkinson’s Progression and to Dementia
- Genetic Testing
Malerba, M., & Ragnoli, B. (2008). Ambroxol in the 21st century: pharmacological and clinical update. Expert Opin Drug Metab Toxicol, 4(8), 1119-1129. doi:10.1517/17425255.4.8.1119
McNeill, A., Magalhaes, J., Shen, C., Chau, K. Y., Hughes, D., Mehta, A., . . . Schapira, A. H. (2014). Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain, 137(Pt 5), 1481-1495. doi:10.1093/brain/awu020
Mullin, S., Smith, L., Lee, K., D'Souza, G., Woodgate, P., Elflein, J., . . . Schapira, A. H. V. (2020). Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. doi:10.1001/jamaneurol.2019.4611
Sanchez-Martinez, A., Beavan, M., Gegg, M. E., Chau, K. Y., Whitworth, A. J., & Schapira, A. H. (2016). Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models. Sci Rep, 6, 31380. doi:10.1038/srep31380