You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.
One of the exciting recent changes in the treatment approach to Parkinson’s disease has been the development of new brain targets that have attempted to move the field beyond the typical dopamine and dopamine agonist-based treatments. One of the brain targets that has gleaned tremendous interest from multiple pharmaceutical companies, as well as from leading scientists from around the world, has been the adenosine A2 receptor. In this month’s What’s Hot column, I will review what is known about this brain receptor, and also provide an update on the status of clinical trials focused on the A2A receptor antagonists for treatment of Parkinson’s disease.
What is the adenosine A2A receptor? There is a group of circuits in the brain called the basal ganglia that are collectively involved in the underlying problems that result in the symptoms of Parkinson’s disease. The basal ganglia have a ton of adenosine A2A receptors located on the outside of nerve cells that are referred to as neurons. Many of these receptors have been observed to be co-located next to dopamine receptors. Scientists believe that you can either activate the dopamine receptor, or alternatively block the adenosine A2 receptor as a means to improving the symptoms of Parkinson’s disease. There has been some speculation that this class of drugs may when used in combination with dopaminergic drugs (e.g. levodopa and agonists) facilitate a reduction in the dosage of dopamine, and a coincident reduction in side effects.
Istradefylline is an adenosine A2A receptor antagonist that has been tried in multiple human studies of patients suffering with Parkinson’s disease. The results of these studies revealed a mild beneficial effect on wearing off and on motor fluctuations. Istradefylline did not achieve FDA approval in the United States, but has been approved for use in Japan. Biotie has been investigating another A2A receptor antagonist for Parkinson’s disease, tozadenant (SYN115). Early treatment results have revealed improvements in off time. Finally, Merck recently investigated another drug named Preladenant. Preladenant is also adenosine A2A receptor antagonist. Early studies revealed promising effects for this compound on PD related “off” periods. Unfortunately, three separate phase III trials did not provide evidence for efficacy over a placebo pill. Vipadenant (BIIB014) and ST-1535 are two A2A receptor compounds that remain under investigation in animal models for Parkinson’s and other diseases. Here I listed other compounds known to block the adenosine A2A receptor, and have been used in various animal and human studies: ATL-444, MSX-3, SCH-58261, 412, 348, 442,416, VER-6623, 6947, 7835, ZM-241,385.
An important point for patients to keep in mind is that the A2A receptor may be affected by the intake of certain foods or drinks. We reported in a previous edition of the What’s Hot Column on recent “animal experiments that have, like in human trials and epidemiological studies, revealed a potential caffeine benefit for Parkinson’s disease sufferers. The benefit is believed to be underpinned by caffeine’s action in blocking the adenosine A2A brain receptor. In humans there have been several small studies and also anecdotal observations that support the idea that there is a mild to moderate caffeine benefit in Parkinson’s.”
It is exciting that pharmaceutical companies and scientists are beginning to look beyond the dopaminergic system for better therapies to treat those suffering from Parkinson’s disease. We should not get too disappointed in the early drug trial failures, as we are just beginning to explore novel and potentially therapeutic areas of the brain that may help this and the next generation of Parkinson’s patients achieve treatment success.
1. Hickey P, Stacy M. Adenosine A2A antagonists in Parkinson's disease: what's next? Curr Neurol Neurosci Rep. 2012 Aug;12(4):376-85. doi:10.1007/s11910-012-0279-2. Review.
2. Federico S, Spalluto G. Therapeutic potential of A2 and A3 adenosine receptor: a review of novel patented ligands. Expert Opin Ther Pat. 2012 Apr;22(4):369-90. doi: 10.1517/13543776.2012.669375. Epub 2012 Mar 22. Review.
3. Kulisevsky J, Poyurovsky M. Adenosine A2A-receptor antagonism and pathophysiology of Parkinson's disease and drug-induced movement disorders. Eur Neurol. 2012;67(1):4-11. doi: 10.1159/000331768. Epub 2011 Nov 30. Review.
4. Armentero MT, Pinna A, Ferré S, Lanciego JL, Müller CE, Franco R. Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson's disease. Pharmacol Ther. 2011 Dec;132(3):280-99. doi:10.1016/j.pharmthera.2011.07.004. Epub 2011 Jul 23. Review.
Posted: 6/4/2013 10:03:57 AM by
Browse current and archived What's Hot in PD? articles, the National Parkinson Foundation's monthly blog for people with Parkinson's written by our National Medical Director, Dr. Michael S. Okun.
Another Setback for Trophic Factor Treatment in Parkinson's Disease
IPX066 and What Patients Really Want in New Carbidopa/Levodopa (Sinemet) Formulations
The Weather Forecast for Parkinson’s Disease Calls for Worldwide Economic Storm
Defeating the Barriers to Implementing Exercise Regimens in Parkinson’s Disease Patients
When should you start medication therapy for Parkinson’s disease?
Neurologist Care Reduces Hospitalizations in Parkinson's Disease
A Victory in Court for Parkinson's Disease Patients who Require Ongoing Rehabilitative Therapies
Given the recent FDA announcement about Mirapex (pramipexole), should I be worried about dopamine agonists?
What about the new Parkinson’s Disease Vaccine? What should I know?
Caffeine as a Potential Treatment for Parkinson’s Disease
Time to Consider GPi DBS for Parkinson’s Disease: A Shift in the Practice of Patient Selection for DBS
A New Treatment for Parkinson’s Disease-Related Constipation
Too Many Pills: Improving Delivery Systems for Parkinson’s Disease Drugs
Measuring Quality and Assessing Depression in Parkinson's Disease
Watch out for Unexpected Obstacles if You Use a Cueing Strategy to Break Freezing of Gait in Parkinson’s Disease
Pill Color, Generic Medications and Insurance Issues: Important Medication-Related Tips for the Parkinson’s Disease Patient
Are Blood Tests for Parkinson’s Disease on the Horizon?
Placing Stem Cells in Animal Models of Parkinson’s Disease: Another Important Step
Important News for the Parkinson’s Disease Community: More Evidence that Sinemet and Madopar are Not Toxic and do Not Accelerate Disease Progression
The Case for All Parkinson’s Disease Patients to be Co-managed by a Primary Care-Neurologist Team
Scientists say Research on Brain Proteins Involved in Parkinson’s Disease is “Shaping” Up
Who Actually Takes Care of Most of the Parkinson’s Patients Worldwide: The Need for Education and the Parkinson’s Toolkit
If you are Dizzy or Passing Out, it could be Your Parkinson’s Disease or Parkinson’s Disease Medications
How Will Group Visits for Parkinson’s Disease Fit into the Future of Parkinson’s Disease Care?
Why Patients Should be Wary of Chelation Therapy for Parkinson’s Disease
Opening the Door to Gene Therapy in Parkinson’s Disease: The Need for Refinement of the Technology and Approach
Does it Matter if I Can’t Get Brand Sinemet?
Should I get a DaTscan or PET scan to confirm my diagnosis of Parkinson’s disease?
A Critical Reappraisal of the Worst Drugs in Parkinson’s Disease
Environmental Risks for PD: Manganese, Welding, Mining, and Parkinsonism
Calling for the FDA to Revise the Eight Sinemet a Day Rule
Dry Cleaning Solvents and Potential Environmental Risks for Developing Parkinson’s Disease
Maintaining the Balance: Why Parkinson’s Disease Patients Need to Understand Drug Recalls, Withdrawals, and Safety Alerts
Shining a Light on Parkinson’s Disease: Optogenetics Has a Bright Future in Research
Poor Medication Management of Parkinson's Disease During Hospital Admissions: Patients and Families Can Improve Their Hospital-Based Management
Why Are Patches and Continuous Release Technology a Big Deal to Parkinson's?
Is the PD SURG Trial Another Surge Forward for DBS Therapy?
Cycling in PD in Those Who Can’t Walk: Is it Possible?
New iPS Stem Cells for PD: What Does it Mean?
Time for Comprehensive Care Networks for PD
Is Parkinson's Disease a Prion Disease?
Parkinson's Disease Linked to Gaucher's Disease
Brain Cells Keep Time Stamps: Implications for Parkinson's Disease Therapies
Is it Safe to Have an MRI with a DBS in Place?
Take Care of Your Bones as They Are Affected in Parkinson's Disease (Even in Men)
Is it Time to Start Paying Attention to Pain Symptoms in Parkinson's Disease Patients?
Glutathione Fails to Demonstrate Significant Improvement in PD Symptoms
Keeping an Eye on Trials Important to the Parkinson's Disease Patient
Increased Risk of Melanoma in Parkinson's Disease
Finally a DBS Expert Consensus Statement Aimed at Their True Customers: The Patients
Pesticides and Environmental Exposure in Parkinson's disease: Should We Stay Away From the Stink Truck?
Is Exercise Effective Treatment and Protection Against PD?
Why are Transplant Trials Struggling to Succeed in the Treatment of PD?
Are Monoamine Oxidase Inhibitors Disease Modifying or Neuroprotective in PD?
Update on Gene Therapy for Parkinson's Disease