The antidepressant drug nortriptyline — approved more than 50 years ago for depression and nerve pain — may also slow the progression of Parkinson’s disease by halting the formation of toxic alpha-synuclein aggregates, say researchers at Michigan State University (MSU).
Their study, “Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form,” appeared in the journal Neurobiology of 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,” MSU neuroscientist Tim Collier, the study’s lead author, said in a news release.
Collier and his team had already found that treatment with nortriptyline — or other antidepressants from the same chemical class — increased the time until levodopa therapy was required. The findings, based on the clinical records of 2,064 Parkinson’s patients, suggested that antidepressants could slow disease progression.
“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.
Next, researchers aimed to learn how exactly these compounds worked in the context of the neurodegenerative disorder. Testing nortriptyline effects in lab-grown cells and in animal models, they found that the drug worked by reducing the amount of misfolded alpha-synuclein and inhibiting the formation of protein aggregates — two well-known hallmarks of Parkinson’s.
In the presence of nortriptyline, alpha-synuclein proteins moved and changed shape much faster, which prevented them from clustering, said Lisa Lapidus, professor at MSU’s Department of Physics and Astronomy, and co-author of the study.
“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,” Lapidus said.
The National Institutes of Health, the Michael J. Fox Foundation, and Saint Mary’s Foundation jointly financed the MSU study. The team now seeks funds to support future human clinical trials exploring the effects of these compounds on Parkinson’s progression.
“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,” said Collier, adding that it remains to be determined whether targeting alpha-synuclein is the optimal approach or if this complex disorder is best served by combination therapies.
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