A New Way to Stop Parkinson's Drug Side Effects Without Brain Surgery

Northwestern Medicine scientists have discovered a way to prevent the involuntary movements that plague Parkinson's patients taking levodopa medication long-term, without requiring brain surgery. The breakthrough targets 'aberrant learning' in the brain that causes these debilitating side effects, potentially keeping patients on their life-changing medication longer.

What Causes These Unwanted Movements in Parkinson's Patients?

About 8.5 million people worldwide live with Parkinson's disease, which destroys brain cells that produce dopamine—a chemical essential for coordinated movement. Levodopa, the go-to treatment, works by converting into dopamine in the brain. But as the disease progresses and more brain cells die, patients need higher doses, and their brains can't regulate dopamine levels properly anymore.

"This symptomatic therapy is recreating a learning signal in the brain that, instead of being dictated by experience or by the need to move, is chemically induced. It's driving aberrant learning, which leads to side effects with prolonged use at high doses," said D. James Surmeier, PhD, the Nathan Smith Davis Professor and chair of Neuroscience who led the study published in Science Advances.

How Does This New Approach Work?

The research team studied mice with Parkinson's-like symptoms and discovered that levodopa treatment creates alternating levels of dopamine and acetylcholine in a brain region called the striatum. This mimics the signals that normally control learning, but in this case, it's teaching the brain the wrong lessons about movement.

The scientists then used two different methods to disrupt the acetylcholine receptors responsible for this faulty learning process. The results were promising:

• Movement Improvement: Disrupting the aberrant learning preserved important brain connections and enhanced levodopa's ability to help patients move normally
• Reduced Side Effects: The severity of levodopa-induced dyskinesia (the medical term for these involuntary movements) was significantly reduced
• Dual Benefits: Patients could potentially get better symptom relief while experiencing fewer unwanted movements from their medication

What Does This Mean for Parkinson's Patients?

Currently, when patients develop these medication-induced movements, they face a difficult choice: reduce their levodopa dose (which worsens their Parkinson's symptoms) or undergo deep-brain stimulation surgery, where electrodes are implanted in the brain.

"Nobody ever wants to have brain surgery, so we've been trying to understand the mechanisms underlying dyskinesia to help us design better pharmacotherapies or gene therapies that don't involve deep brain stimulation," Surmeier explained.

This new understanding could lead to treatments that use genetic approaches or targeted medications to block the aberrant learning process. "What our study suggests is that the symptomatic treatment of late-stage patients leads to aberrant learning in the striatum. What we found is that if we disrupt that aberrant learning, we increase the symptomatic benefit of levodopa and at the same time diminish the dyskinesia," Surmeier said.

While this research is still in the laboratory stage using mouse models, it offers hope for developing new therapies that could help Parkinson's patients avoid both worsening symptoms and invasive brain surgery. The approach represents a fundamental shift from managing symptoms to addressing the underlying brain processes that create medication side effects.