Trailblazing medical researcher Dr. Jonathan Sackner-Bernstein offers a new theory about the causes (and potential treatments) for Parkinson’s, which could upend the prevailing treatments for the disease.
This week The Journal of Parkinson’s Disease published a peer-reviewed scientific study by Dr. Jonathan Sackner-Bernstein positing that the standard way to treat Parkinson's might be precisely the opposite of what would be the most effective. The data in this new study show that instead of focusing on increasing brain dopamine in Parkinson’s patients, a more scientifically rational approach would be to reduce the amount of dopamine within the cells in the brain that control movement.
Data from the study of human brain tissue includes many different types of cells and the materials that connect and bathe the cells. Sackner-Bernstein’s analysis confirmed the marked reduction in tissue dopamine, by 82% in the caudate and 96% in the putamen – the two areas of the human brain most affected by Parkinson’s.
However, the toxicity of dopamine relates to the amount within the dopaminergic brain cells, rather than the concentration surrounding them. To rationally select a therapy, doctors need to know the levels dopamine inside these cells rather than what happens around these cells. This analysis reports that the dopamine levels in the cytosol of these cells – the part of the brain cells where dopamine produces its toxicity – were 1.9 times and 4.6 times higher than normal in the caudate and putamen of the brain in patients with advanced Parkinson’s disease.
Prior to this publication by Sackner-Bernstein, the amount of dopamine inside these vital brain cells had never been reported.
Along with the elevated dopamine levels inside these cells, these brain cells in people with Parkinson’s disease cannot protect themselves from dopamine toxicity. Thus, the toxic effects of dopamine are more pronounced on the very cells people need the most when suffering from Parkinson's.
As Sackner-Bernstein explained, “The function and viability of the nerve cells is what determines the severity and progression of Parkinson’s disease. Because dopamine can be toxic to these nerve cells, scientists and clinicians cannot develop or prescribe therapies to reverse the disease without knowing the amount of dopamine within these cells. For the first time, these new data show us what is going on inside the brain cells that need the right treatment.”
The study’s findings explain why treatments to increase dopamine don’t slow or reverse disease progression. Sackner-Bernstein continues, "There is already more than enough dopamine inside the cells. In some ways, using dopaminergic therapies is akin to whipping a tired horse; it helps for a few strides but doesn’t affect long-term results."
Four laboratory studies report that blocking production of dopamine within these brain cells improves cell function and keeps them alive. Such data in the context of this new observation of increased intracellular dopamine establish a new therapeutic path – one that reduces the average level of dopamine in the nerve cells, while preserving the cells’ ability to synthesize dopamine when needed. This approach can be tested now by using the drug metyrosine to partially block the synthesis of dopamine within the nerve cells.
“We’ve lived in the dopaminergic era since the 1970s and that has allowed for millions of people with Parkinson’s to feel some improvement in their symptoms. Yet the disease worsens inexorably. It’s time to test a new approach, one based on firm science as highlighted by this groundbreaking publication. The clinical trial to assess the potential impact of blocking dopamine could start this year,” concluded Sackner-Bernstein.
About the History of Parkinson’s Treatments
Using drugs to increase brain dopamine has been the standard since the 1970s, when several studies showed that the total amount of dopamine in the brain tissue was low and several other studies reported that increasing brain dopamine levels resulted in rapid and noticeable improvement in mobility for patients with Parkinson’s. Unfortunately, no drug that increases dopamine produces long-lasting improvement in symptoms. And none of the treatments in use today slow or reverse the inevitable worsening of the disease.
Scientists have shown over and again that if brain cells have too much dopamine, this critical chemical becomes toxic to these very cells, causing brain cell dysfunction and cell death. Yet despite this risk of excess dopamine, prior to this study by Sackner-Bernstein, no one has reported the amount of dopamine within these brain cells. These findings have important implications on why current therapies are not more effective and on how to develop new treatments.
About Dr. Sackner-Bernstein
Jonathan Sackner-Bernstein, MD, formerly a senior official at the United States Food and Drug Administration, gained international acclaim when he used publicly available data to demonstrate the lack of efficacy of a multibillion-dollar cardiac drug. Previously, he played a central role in the development of beta-blockers for heart failure, starting at a time when they were contraindicated and ending in proof that beta-blockers improved symptoms and survival for patients with heart failure. Sackner-Bernstein helped DARPA launch its Biological Technologies Office with its research program focused on medicine and biology, with its emphasis on neurosciences.