Brain’s Brake and Accelerator Must Cooperate to Avoid Side Effects of Parkinson’s Treatment

An optimal Parkinson’s disease treatment would need to target both accelerator and brake functions in the brain to be effective without producing side effects like the jerky movements associated with L-dopa treatment.

Using an advanced method to manipulate the activity in the two brain pathways that act as the accelerator and brake in movement control, a research team discovered that both pathways are involved in all types of movement, and so a balance between the two actions is needed.

The findings have great implications for the development of Parkinson’s treatments, showing that side effects in the form of uncontrolled jerky motions cannot be avoided if a drug does not target both nerve pathways.

The study, “Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy,” was published in the Journal of Clinical Investigation.

In a brain area called the striatum, two nerve bundles are known to regulate movement. The so-called direct pathway is usually described as the accelerator, while the indirect pathway acts as a brake.

While researchers have long known about the existence of the nerve pathways, scientists had not agreed if the pathways are equally important in various types of movement, and if they need to work together or can act independently.

“We know that the striatum plays an important role in movement control. But which neural pathways are most important has been hotly debated,” Angela Cenci Nilsson, the study’s senior investigator, said in a press release.

Using a relatively new method called chemogenetics, researchers at Lund University in Sweden were able to determine the importance of the two nerve bundles. They introduced a new gene into cells of either the direct or indirect pathways in mice. This gene could activate the cell, but only when mice were given a particular drug.

In this way, the team could turn on one of the pathways for a few hours while the mice performed different tasks. The team tested both normal and Parkinson’s disease mice, both untreated and treated with L-dopa.

They found that both pathways were needed in all situations. In the treated Parkinson’s mice, activating the accelerator pathway sped up the mice movements but also produced the jerky motions seen in patients receiving the treatment.

When the researchers activated the indirect pathway in the Parkinson’s mice receiving L-dopa, the jerkiness was reduced, but the movements also became slower.

“We interpret these results to mean that the pathways need to interact in all situations, even in Parkinson’s-like conditions and upon L-dopa treatment. You can’t have only acceleration and no braking, but must instead balance both functions in a precise manner,” Cenci Nilsson said.

She is convinced that L-dopa gives rise to side effects when it inactivates the brake while activating the accelerator too much. This would also indicate that any Parkinson’s drug would need to act in a balanced way on both pathways to prevent the side effects.

“Our results could be of great significance both for basic research and for therapeutic research,” Cenci Nilsson said.