Parkinson’s disease affects the nervous system and causes muscle stiffness, slow imprecise movement and uncontrolled shakes, mainly in elderly and even middle-aged people. Dopamine is an essential neurotransmitter that allows neurons to “talk” to each other and the loss of dopamine producing neurons (brain cells) causes Parkinson’s disease.
Two caffeine-based chemical compounds have recently been developed by researchers from the University of Saskatchewan. A protein called α-synuclein (AS) is involved in dopamine regulation and was the focus of the research. The team believe their compounds show promise in preventing the ravages of Parkinson’s disease.
In people with Parkinson’s, dopamine-producing neurons die because AS is misfolded into a compact structure. “Mad cow disease” or variant Creutzfeldt-Jacob is classified as a prion disease. In prion diseases, one misfolded protein triggers misfolding in others, spreading like falling dominos. To make things worse for Parkinson’s sufferers, AS appears to act the same as a prion disease.
The team was led by Ed Krol from the College of Pharmacy and Nutrition and a biochemist from the University of Saskatchewan’s College of Medicine, Jeremy Lee. Other team members included Kevin Allen from the Drug Discovery and Research Group in the College of Pharmacy and Nutrition, and Joe Kakish and Troy Harkness from the U of S College of Medicine.
Lee explained that the team decided to adopt a different approach than current therapeutic compounds do. Instead of trying to boost the dopamine output of surviving cells, they focused on protecting dopamine-producing cells. The aim is to prevent α-synuclein from misfolding in the first place. Current treatments are only effective as long as there are still enough cells that produce dopamine. `
The chemistry for this solution was challenging. The researchers synthesized 30 different “bifunctional dimer” drugs. These drugs contain molecules that link two different substances that are known to affect cells producing dopamine. Steered by literature that shows a caffeine “scaffold” that protects against Parkinson’s, the team added other compounds with known effects. These included aminoindan, a research chemical similar to the Parkinson’s drug rasagiline, the diabetes drug metformin and nicotine.
The team discovered that two of the compounds prevented the AS protein from clumping in a yeast model of Parkinson’s disease, and allowed the cells to grow normally. Lee is optimistic that these bifunctional dimers show promise in preventing the progression of Parkinson’s disease.
The findings are published in the journal ACS Chemical Neuroscience.