Summary: According to researchers, an antidepressant that has been available for more than 50 years could help slow the progression of Parkinson’s disease. The drug, nortiptyline, has been shown to stop the growth of alpha synuclein.
Source: Michigan State University.
Michigan State University scientists now have early proof that an antidepressant drug that’s been around for more than 50 years could slow the progression of Parkinson’s.
In a proof-of-concept study, published in the journal Neurobiology of Disease, the drug nortriptyline, which has been used to treat depression and nerve pain, stopped the growth of abnormal proteins that can build up in the brain and lead to the development of the disease.
“Depression is a very frequent condition associated with Parkinson’s, so we became interested in whether an antidepressant could modify how the disease progresses,” said Tim Collier, lead author of the federally funded study and a neuroscientist at MSU.
Collier and collaborator Katrina Paumier, an assistant professor of molecular medicine, began looking at previous patient data to see if individuals who were on antidepressants experienced any delay in their need to go on a standard Parkinson’s therapy called levodopa. This type of therapy increases levels of dopamine, a natural chemical in the body that sends signals to other nerve cells and can significantly decrease in cases of Parkinson’s.
The medication also treats many of the symptoms associated with the disease such as tremors and poor muscle control.
“We found that those on a certain class of antidepressant, called tricyclics, didn’t need the levodopa therapy until much later compared to those who weren’t on that type of antidepressant medication,” Collier said.
Collier then began testing rats with the tricyclic antidepressant nortriptyline and found that it indeed was able to decrease the amount of abnormal protein that can build up in the brain. This protein, known as alpha-synuclein, can cause the brain’s nerve cells to die when in a clustered state and is a hallmark sign of the disease.
To further back up his research, he enlisted the help of his colleague and co-author Lisa Lapidus, who in previous studies had already detected whether certain compounds could bind to alpha-synuclein and stop it from accumulating.
“Proteins are constantly moving and changing shape,” said Lapidus, a professor in the Department of Physics and Astronomy. “By using a test tube model, we found that by adding nortriptyline to the alpha-synuclein proteins, they began to move and change shape much faster, preventing the proteins from clumping together. The idea that this clustering effect is controlled by how fast or slow a protein reconfigures itself is typically not a standard way of thinking in research on proteins, but our work has been able to show these changes.”
Understanding how these proteins can clump together could point researchers in new directions and help them find other possible drugs that could potentially treat Parkinson’s.
“What we’ve essentially shown is that an already FDA-approved drug that’s been studied over 50 years and is relatively well tolerated could be a much simpler approach to treating the disease itself, not just the symptoms,” Collier said.
Collier is already looking for funding for the next phase of his research and hopes to lead a human clinical trial using the drug in the future.
Funding: The National Institutes of Health, as well as the Michael J. Fox and St. Mary’s Foundations, funded the study.
Source: Sarina Gleason – Michigan State University
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form” by Timothy J.Collier, Kinshuk R.Srivastava, Craig Justman, Birgit Hutter-Paier, Manuela Prokesch, Daniel Havas, Jean-Christophe Rochet, Fang Liu, Patríciade Oliveira, Georgia L.Stirtz, Ulf Dettmer, Caryl E.Sortwell, Mel B.Feany, Peter Lansbury, Lisa Lapidus, and Katrina L.Paumier in Neurobiology of Disease. Published online July 12 2017 doi:10.1016/j.nbd.2017.07.007
Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form
The pathology of Parkinson’s disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of α-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein. We go on to demonstrate that NOR inhibits the accumulation, aggregation and neurotoxicity of α-syn in multiple cell and animal models. These findings suggest that NOR, a compound with established safety and efficacy for treatment of depression, may slow progression of α-syn pathology by directly binding to soluble, native, α-syn, thereby inhibiting pathological aggregation and preserving its normal functions.
“Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form” by Timothy J.Collier, Kinshuk R.Srivastava, Craig Justman, Birgit Hutter-Paier, Manuela Prokesch, Daniel Havas, Jean-Christophe Rochet, Fang Liu, Patríciade Oliveira, Georgia L.Stirtz, Ulf Dettmer, Caryl E.Sortwell, Mel B.Feany, Peter Lansbury, Lisa Lapidus, and Katrina L.Paumier in Neurobiology of Disease. Published online July 12 2017 doi:10.1016/j.nbd.2017.07.007