Innovations in treating Parkinson's disease

Almost 90,000 people in the U.S. are diagnosed with Parkinson’s disease every year, making it the second-most common neurodegenerative disease following Alzheimer’s. The causes of Parkinson’s are complex, ranging from genetic factors to environmental factors and toxin exposure. The primary risk factor, however, is aging. As the population ages and more people are subject to its effects, cases are expected to rise.

We examined the CAS Content Collection to better understand trends in Parkinson's-related research, and we found that connections between other diseases and Parkinson's is a growing field of interest. Not only are new drugs and treatments in development, but drug repurposing — leveraging existing drugs with known safety profiles and mechanisms of action — is being pursued to tackle not just the symptoms but the underlying causes. The challenge is significant, but new breakthroughs may be on the horizon.

Risk factors of Parkinson’s disease and pathophysiology

The hallmark feature of Parkinson's is dopamine neurodegeneration — the progressive loss of dopamine-producing neurons in the substantia nigra, a region of the brain involved in movement control. Dopamine is a neurotransmitter that plays a critical role in regulating motor function and coordination. Its depletion leads to the characteristic motor symptoms of Parkinson's, such as tremors, rigidity, and bradykinesia (slowness of movement).

As noted, aging is the primary risk factor for developing Parkinson's. Most cases are sporadic but a small percentage, about 5-10%, are believed to have a genetic component. Mutations in the SNCA (α-synuclein), LRRK2 (leucine-rich repeat kinase 2), Parkin (PARK2), PINK1 (PARK6), and DJ-1 (PARK7) genes have been implicated as disrupting protein degradation processes, mitochondrial functions, and oxidative stress response in familial Parkinson's cases.

There are also environmental and lifestyle factors that may play a role in Parkinson's, although research is still in its nascent stages. Exposure to pesticides, herbicides, heavy metals, and contaminated drinking water may increase the risk of developing Parkinson's, as can lifestyle factors that contribute to chronic inflammation and oxidative stress, such as poor diet and lack of exercise.

The resulting pathophysiology of Parkinson's includes:

• Degradation of dopamine neurons.
• Accumulation of Lewy bodies, a type of misfolded α-synuclein protein found in regions of the brain involved in motor and cognitive functions.
• Chronic inflammation and oxidative stress, which lead to neuronal damage and exacerbate neuronal dysfunction.
• Dysfunction of mitochondria and protein clearance mechanisms.

Current trends in Parkinson’s disease research

There are over 220,000 scientific publications in the CAS Content Collection relating to Parkinson's, and the number has grown more than 30% since 2019. Journals dominate the field with a journal-to-patent ratio of about 4-6, but in the last few years, patent publications have noticeably increased, suggesting that more therapies are coming to market (see Figure 1).

We analyzed the research as it relates to Parkinson's pathophysiology and found that the largest portion of Parkinson's-related documents address genetic factors. However, mitochondrial dysfunction, neuroinflammation, and environmental factors are the fastest-growing subject areas (see Figure 2).

This is important because a better understanding of external risk factors like environmental exposure can raise awareness for proactive health measures and preventive strategies. Armed with this information, healthcare providers will also be better equipped to tailor prevention and treatment strategies to each patient’s unique profile.

Aging is the most widely explored concept in Parkinson's-related literature, and we noted in our analysis that there is a significant overlap between the hallmarks of Parkinson's and aging, namely mitochondrial dysfunction, inflammation, and impaired protein clearance (see Figure 3).

Disease co-occurrence and potential drug therapies for Parkinson’s disease

The connection between neuroinflammation and Parkinson's has opened up a field of research into the comorbidities that drive inflammation and oxidative stress. Therefore, they may exacerbate the risk of developing the disease. For example, proinflammatory cytokines cause modifications in serotonin and dopamine neurotransmission leading to Parkinson’s and depression; several studies have shown that patients with Parkinson's frequently suffer from depression.

Cardiovascular diseases, obesity, and type II diabetes all lead to chronic inflammation and oxidative stress. Many other chronic diseases influence these risk factors — kidney and liver diseases cause inflammation and oxidative stress, as do respiratory diseases, like CO, Parkinson's, and autoimmune diseases. Cancerous tumors can also induce issues in surrounding tissues.

Researchers are examining if drug therapies for these comorbidities could be repurposed to treat Parkinson's. Overall, repurposing drugs is a promising strategy for finding breakthroughs because existing drugs have well-established safety profiles. This means significant savings in time and cost to bring them into clinical use, and there are lower risks of negative side effects.

Repurposing existing drugs that address neuroinflammation and oxidative stress in any disease may lead to treatments for the causes of Parkinson's, not just the symptoms, which would be a true game-changer for fighting this disease. Because of this, we see neuroprotective agents as the most commonly occurring drugs explored for repurposing (see Figure 4).

Our analysis of the CAS Content Collection has further identified the following categories of repurposed drugs and why they are of interest in Parkinson's research:

• Hypertension drugs: Some hypertension medications may have neuroprotective effects or influence dopamine signaling, which is impaired in Parkinson's patients.
• Antidepressants: Certain antidepressants may modulate neurotransmitter systems implicated in Parkinson's pathophysiology.
• Cancer drugs: There are cancer medications that target inflammation or cell growth pathways that may be relevant to treating Parkinson's progression.
• Infection drugs: Some antibiotics and antivirals may have beneficial anti-inflammatory properties.
• Diabetes treatments: Glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed for the treatment of type II diabetes, have shown promise for their neuroprotective effects in Parkinson's.

In addition to re-purposed drugs, there are small molecules, monoclonal antibodies, and cellular therapies in clinical trials. Exemplary drugs are listed in Table 1:

Potential breakthroughs to watch in Parkinson’s research

Drug repurposing and development are exciting areas of Parkinson's research, but scientists are also pursuing new breakthroughs in diagnosis and other forms of treatment. For example, advances in imaging technology, molecular biology, and big data analytics hold promise for identifying biomarkers that can improve early diagnosis, monitor disease progression, and evaluate treatment responses.

An ongoing challenge in treating Parkinson's is the difficulty in getting drug molecules to cross the blood-brain barrier. Emerging nanotechnologies may revolutionize this type of drug delivery in the near future. Polylactic-co-glycolic acid (PLGA) nanoparticles loaded with L-DOPA have reportedly increased motor function in Parkinson's patients, and ongoing research is identifying nanoparticle materials that can successfully deliver these medications across the blood-brain barrier.

Lastly, numerous advanced therapies are in development, including the tailoring of gene therapy for personalized medicine. As seen in Figure 5, we noted thousands of documents in the CAS Content Collection related to major genes involved in familial Parkinson's and found three (PARK2, PINK1, and GBA) that show the highest growth in research.

Deep brain stimulation is another treatment to watch — this involves implanting electrodes into specific brain regions and delivering electrical impulses to modulate abnormal neuronal activity. The FDA also recently approved a focused ultrasound treatment named Exablate Neuro to treat Parkinson's symptoms.

Parkinson's is one of the most challenging diseases associated with aging. However, the research landscape is robust, from developing an understanding of disease co-occurrences and potentially repurposing existing safe medications, to finding genetic breakthroughs and cutting-edge treatment methods. Hopefully these efforts will lead to advances in not just treating Parkinson's symptoms, but in addressing the root causes of the disease, thereby bringing hope to millions of people worldwide.

For deeper insight into the landscape of neurodegenerative diseases, see our recent report on Alzheimer's, Parkinson's, and Huntington's diseases.

Key data in this article as well as Figures 1-5 are extracted from Tenchov R, Sasso JM, Zhou QA. The Evolving Landscape of Parkinson's Disease Research: Current Challenges and Future Outlook. ChemRxiv. 2024; 10.26434/chemrxiv-2024-fp9nj.