Caffeine Derivatives Treat Parkinson’s Disease

Two chemical substances from caffeine were discovered to exhibit promise in preventing the development of Parkinson's disease along with its devastating signs and symptoms. Parkinson's disease attacks the body's nervous system, inflicting uncontrolled shakes, muscle stiffness, and sluggish, imprecise movement, particularly in middle-aged and elderly persons. It is usually prompted by the damage of brain cells (neurons) that produce dopamine, an principal neurotransmitter that allows for neurons to talk to one another.

A team of researchers from the University of Saskatchewan has discovered and developed two caffeine-derived chemical substances that show promise in stopping the devastating effects of Parkinson’s disease.

The team studied the characteristics of a protein known as a-synuclein (AS), which is involved in dopamine regulation.

A-synuclein

In people with Parkinson’s disease, AS can be misfolded into a compact structure, which is associated with the demise of dopamine-producing neurons. AS also appears to behave like a prion disease similar to that of variant Creutzfeldt-Jacob or “mad cow” disease. In prion diseases, one misfolded protein can lead to the misfolding of others, so that the disease easily spreads.

The investigators of these study were Jeremy Lee, a biochemist from the U of S College of Medicine, and Ed Krol from the College of Pharmacy and Nutrition, along with researchers Troy Harkness and Joe Kakish from the U of S College of Medicine, as well as Kevin Allen from the Drug Discovery and Research Group in the College of Pharmacy and Nutrition.

According to Lee, Many of the current therapeutic compounds focus on boosting the dopamine output of surviving cells, but this is effective only as long as there are still enough cells to do the job. Our approach aims to protect dopamine-producing cells by preventing a-synuclein from mis-folding in the first place.

Caffeine Scaffold

Despite the fact that the chemistry was challenging, Lee explained that the research team synthesized 30 special “bifunctional dimer” drugs, which are molecules that link two different substances identified to influence dopamine-producing cells.

They started with a caffeine “scaffold,” guided by using literature that suggests the stimulant has a protective outcome against Parkinson’s. From this base, they added different compounds with known effects: nicotine, the diabetes drug metformin, and aminoindan, a research chemical much like the Parkinson’s drug rasagiline.

Using a yeast model of Parkinson’s disease, Lee and his team learned that two of the compounds prevented the AS protein from clumping, and without problems permitted the cells to grow and develop normally. Lee added, Our results suggest these novel bifunctional dimers show promise in preventing the progression of Parkinson’s disease.

Their findings are published in the journal ACS Chemical Neuroscience.