Parkinson’s: New approach stimulates ‘sonic hedgehog’ protein pathway
- Globally, levodopa (or L-dopa) is the gold standard for treating Parkinson’s disease.
- However, continuous use results in side effects that cause involuntary body movements. This is known as levodopa-induced dyskinesia (LID).
- One way to correct LID is an invasive procedure called deep brain stimulation. However, this option is time consuming, and not everyone is eligible for the procedure.
- Now, a new study in rodents and nonhuman primates suggests that drugs that increase the signaling of a protein called sonic hedgehog could attenuate the effects of LID.
- The results may unlock potential treatment options previously unavailable to some people living with Parkinson’s disease.
Parkinson’s disease is a neurodegenerative condition that mostly affects body movement. It occurs as a result of the deterioration of the cells in a part of the brain called the substantia nigra.
The substantia nigra produces dopamine, which affects movement control, cognitive functions, and emotional activity. Consequently, the symptoms of Parkinson’s disease include:
- tremor
- muscle stiffness
- difficulty coordinating movements
- sleep problems
- mood changes
Currently, L-dopa — which is converted to dopamine in the body — is the treatment drug of choice for Parkinson’s disease. However, prolonged use elicits side effects characterized by involuntary body movements collectively called LID.
One of the most effective ways to treat LID is through a surgical procedure known as deep brain stimulation.
During deep brain stimulation, a healthcare professional places a medical device inside the body and connects it to the brain using tiny electrodes. The device generates electrical impulses that block or modify involuntary movements that arise due to the symptoms of LID.
However, some studies suggest that not everyone living with Parkinson’s disease qualifies for this treatment.
To address this issue, Dr. Andreas Kottmann, Ph.D., an associate professor at the CUNY School of Medicine at City College New York, and colleagues carried out a new study.
Dr. Kottmann and team set out to explore new avenues of investigation and potential treatment options for the symptoms of LID.
They recently published their results in the journal Communications Biology.
Testing the sonic hedgehog hypothesis
The researchers based their hypothesis on the protein sonic hedgehog (Shh). This is a chemical signal important for the development of the brain and spinal cord, and it is also involved in motor skill learning.
First, they hypothesized that Shh is crucial to motor skill learning and that diminished expression of Shh due to the degeneration of dopamine neurons facilitates the formation and expression of LID.
Next, using animal models, they tested whether or not a synergistic relationship between L-dopa and Shh agonists could reverse the formation and appearance of LID. They used three different models of Parkinson’s disease to investigate this.
At the beginning of the study, the researchers used rodents and nonhuman primate models. They genetically modified the brains of the animals in the test group to produce Parkinson’s-like symptoms. The animals then received intense L-dopa treatment over a couple of weeks.
During the treatment, the scientists administered several behavioral tests to check for symptoms of LID in the animals. Once LID was confirmed, the experimenters introduced Shh agonists to the L-dopa treatment, and they noted the corresponding results.
As well as the behavioral tests, the researchers harvested tissue samples from the brains of the animals. They did this to study the impact of LID and Shh agonists on the structure and proper functioning of this tissue.
The scientists compared all test results against a control group.
Interpreting the test results
The results indicated that reduced signaling of Shh combined with increased dopamine from L-dopa helped in the formation and expression of LID. Conversely, increased signaling of Shh alongside dopamine from L-dopa relieved symptoms of LID.
In other words, low levels of Shh encouraged LID formation, and high levels of Shh reversed LID symptoms.
Interestingly, the scientists also noticed that following severe reduction of Shh from dopamine neurons, and in the absence of L-dopa, the non-Parkinson’s mice also experienced LID-like involuntary movements.
These findings led the scientists to conclude that exploring Shh agonists could be a promising therapeutic approach in the development of anti-LID medications.
Medical News Today reached out to experts to seek their opinion on the study.
Dr. Rebecca Gilbert, Ph.D., the chief scientific officer at the American Parkinson Disease Association, explained that the clear clinical implications from the study could greatly help people with Parkinson’s disease who experience LID.
However, she also sounded a note of caution. “Research is a slow process, which can understandably be frustrating for those affected by [Parkinson’s disease].”
“The development of a drug that reduces [LID] based on Dr. Kottmann’s work will need many more years of work to come to fruition,” she added.
“However, Dr. Kottmann’s avenue of understanding dyskinesias is a new and exciting approach that should bring hope to anyone who is dealing with this difficult problem,” Dr. Gilbert concluded.
Cautious optimism
This study had many strengths, but it was not without limitations. MNT reached out to Dr. Kottmann to learn about them.
He said, “The biggest limitation is that the drugs used in this study likely cannot be directly used in patients due to their strong cancer-inducing potential.”
Regardless, Dr. Kottmann is not overly concerned. He explained that the study results provide a stronger reason for exploring the Shh signaling pathway to develop effective anti-LID drugs without cancer-inducing abilities.
It is safe to expect more answers from Dr. Kottmann and his team in the coming years.
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