Researchers at Northwestern Medicine have found a new avenue for improving the treatment of Parkinson's disease. By intervening in derailed learning processes in the brain, the effectiveness of levodopa, the most commonly used first-line treatment, may be increased and serious side effects reduced.
The research, recently published in Science Advances, is led by D. James Surmeier, professor and chair of the Department of Neuroscience. The core of the finding: long-term use of levodopa in patients with advanced Parkinson's disease can lead to abnormal learning mechanisms in the striatum, a brain area that is crucial for controlling purposeful movements and habits. It is precisely these derailed learning processes that appear to be a major cause of therapy-related side effects, such as involuntary movements.
Surmeier explains: ‘This symptomatic therapy mimics a learning signal in the brain that is normally controlled by experience or the need for movement, but is now chemically induced. This causes derailed learning, which leads to side effects with long-term use and high doses. We wanted to block that abnormal learning process and thereby reduce the side effects of the treatment.’
Limitations of Levodopa
Levodopa remains the cornerstone of Parkinson's treatment, but it has its limitations. An estimated 8.5 million people worldwide live with Parkinson's disease. The condition is characterised by the loss of dopaminergic neurons in the midbrain, which disrupts the control of movements and habits. In the early stages, symptoms such as tremors, muscle stiffness and slowness can usually be effectively suppressed with medication. However, as the disease progresses, the effectiveness of this medication decreases and side effects become more common.
One of the biggest problems in the later stages is levodopa-induced dyskinesia (LID): involuntary, often violent movements that occur as a side effect of the medication. Levodopa is converted into dopamine in the brain and thus acts as a replacement for the missing neurotransmitter. However, as more dopaminergic neurons are lost, the regulation of dopamine is disrupted. This leads to large fluctuations in dopamine concentration in the brain, which is strongly associated with the development of dyskinesias. ‘When those neurons disappear, dopamine metabolism is no longer properly regulated,’ says Surmeier. ‘Paradoxically, this leads to unwanted movements.’
At this stage, patients often have only two options: reducing the levodopa dosage, resulting in increased motor limitations, or undergoing deep brain stimulation, a radical neurosurgical treatment. ‘No one likes to opt for brain surgery,’ says Surmeier. ‘That's why we're looking for pharmacological or genetic alternatives that offer the same benefits without invasive procedures.’
Combined research
In the current study, the team combined electrophysiological, pharmacological, molecular and behavioural techniques in a mouse model of Parkinson's disease treated with levodopa. The researchers focused on spiny projection neurons, the main neuron population in the striatum involved in motor control.
The researchers discovered that in Parkinson's-like mice, the concentrations of dopamine and acetylcholine in the striatum alternated in a way that normally controls learning processes and synaptic plasticity. In this case, however, that alternation led to abnormal learning.
The researchers then used genetic and pharmacological methods to disrupt specific acetylcholine receptors that are necessary for these learning processes. By simultaneously monitoring the behaviour and movements of the mice, they were able to determine the effect on the severity of dyskinesias.
Promising results
The results were promising: interrupting this cholinergic signalling protected the synaptic connections in the affected neurons, improved the motor response to levodopa and reduced the severity of the dyskinesias.
According to Surmeier, these findings open the door to new treatment strategies. By specifically targeting the derailed learning mechanisms in the striatum, the symptomatic effect of levodopa can be enhanced while reducing side effects. This could reduce the need for deep brain stimulation. ‘Our study shows that treating patients at a late stage leads to abnormal learning in the striatum,’ concludes Surmeier. ‘By disrupting that process, we increase the therapeutic effect of levodopa and reduce dyskinesia at the same time.’
The results emphasise the importance of a deeper biological understanding of therapy-related side effects and fit into a broader trend towards more targeted, mechanism-driven treatments for neurodegenerative disorders.
