Research

Parkinson’s Disease: Exploring Levodopa’s Effectiveness as a Treatment

Bibek Samal


Abstract

Treating Parkinson’s Disease has always been a struggle for clinicians and researchers, as there still is no known cure for the disease. A Parkinson’s diagnosis often implies a lifetime of medications and physical therapy. For many years, chiefly one treatment has been proven as immensely successful in inhibiting some of the symptoms associated with Parkinson’s for certain periods of time. This therapy, termed levodopa (L-Dopa) therapy, the brainchild of pharmacologist Arvid Carlsson, has been held to a high standard of symptomatic inhibition by increasing dopamine concentration, the primary neurotransmitter associated with movement. In addition to levodopa, there are other treatments, such as deep brain stimulation, and medications, such as benztropine and selegiline (an anti-tremor medication and antidepressant respectively) [6]. This article aims to highlight the effectiveness of L-Dopa as a treatment for Parkinson’s and also study some of the other medications and therapies that are being used to combat the disease and their viability. 

 

Background & Physiology

Parkinson’s Disease is a neurodegenerative motor disease associated with the central nervous system, inhibiting movement. A review of the pathophysiology of Parkinson’s shows the buildup of misfolded proteins called Lewy bodies, which consist of alpha-synuclein {1}. This near-fatal disease works by degenerating the region of the brain called the substantia nigra, which is connected with the basal ganglia, the brain’s region associated with behavior and movement. This degeneration leads to the death of motor neurons, nerve cells necessary for movement, and eventually results in some of the common motor-impaired symptoms such as tremors, balance problems, and bradykinesia (a slowness of movement) [1].

Although no cure is available, treatments have been introduced for Parkinson’s, the most prevalent approach being the use of levodopa. Currently, the use of levodopa is regarded as the foremost approach to treating Parkinson’s disease. Levodopa functions by crossing the blood-brain barrier and increasing dopamine concentrations in order to promote movement {2}. In Parkinson’s patients, dopaminergic neurons eventually die, thus not generating movement within the body {2}. This inability to generate movement is what leads to the degeneration of motor neurons and introduction of motor symptoms within the substantia nigra. By stimulating dopamine generation, this medical therapy is a key contributor to restoring movement in patients. Similarly, other options are becoming more widely known and tested such as deep brain stimulation and dopamine agonists [2] .

These recent and experimental treatments target areas of the brain such as the subthalamic nucleus and adjacent regions in order to test the effectiveness in areas different from the substantia nigra. The next sections examine the benefits of the mentioned treatments and how each approach is applied to the different range of symptoms that the patient experiences.

 

Choice of Treatment Based on Stage

Not every treatment will have the same effect on patients based on their symptoms. Treatments and approaches are best modeled for the patient based on the progression and stage of the disorder. Parkinson’s Disease usually occurs in 5 stages with increasing severity of symptoms in each stage.

The first stage is characterized as very mild and includes symptoms such as a light tremor, rigidity, and stiffness on one side of the body. In this stage, symptoms occur very mildly, thus the doctor may wait for symptoms to progress in order to make a clear diagnosis. Because of this, seldom any medications are prescribed in this stage. Moving into stage 2, symptoms start to appear bilaterally (on both sides of the body), introducing the difficulty of moving and more apparent tremors. Stages 3 through 5 continue the progression of the appearance of tremors and increased loss of balance. These stages mark the increasing difficulty of movement and inhibition of basic motor tasks such as voluntarily grasping and walking {7}. 

Starting with the first two stages, theoretically, the most used approaches are levodopa therapy and carbidopa. Levodopa acts as the primary line of medications after diagnosis and treats the wide range of symptoms throughout the stages. Since levodopa increases dopamine levels in the brain, this lowers the occurrence of akinesia, the symptom of jerking involuntary movements. Similarly, levodopa also helps to treat the primary symptom of tremors that is more widely observed. However, levodopa also causes side effects such as vomiting and nausea, which occur due to the added depletions of “serotonin, thiols, l-tyrosine, and l-tryptophan”, resulting in a nutritional deficiency {1}. Because of this, levodopa is usually paired with carbidopa, a decarboxylase inhibitor, which inhibits pyridoxal 5′- phosphate-dependent enzymes, decreasing the risk of nausea {3}. However, just as levodopa has downsides by acting without carbidopa, carbidopa has significant downsides as well, causing the fatal symptom of irreversible dyskinesia. Dyskinesia refers to the uncontrolled, involuntary movements that patients feel during the onset of Parkinson’s. According to Hinz, Stein, and Cole, “Research into the phenomenon led to the formulation of the hypothesis that if significant depletion of histamine induces dyskinesias, then carbidopa is capable of inducing dyskinesias, which if not managed properly may be perceived as irreversible” {3}. Thus, this establishes carbidopa is a histamine depleting agent, which is the cause behind the increase of dyskinesias.

 

Levodopa’s Toxicity and Other Advanced Symptoms

Moving forward, levodopa has significant downsides even though it is regarded as the key player in the fight against Parkinson’s. For example, levodopa is a nausea-inducing agent, needing to be paired up with carbidopa in order to prevent its breakdown before crossing the blood-brain barrier and losing effectiveness. Following this, levodopa has also had a history of accelerating or increasing the occurrence of certain symptoms of Parkinson’s Disease, such as dyskinesia. Looking at one instance, “In the early 1990s, a number of in vitro studies demonstrated that high doses of LD can be toxic to dopaminergic neurons in cell culture, causing some PD specialists to recommend withholding LD for as long as possible” {2}. This signifies that levodopa has an optimal dosage at which it performs the most effectively, decreasing its therapeutic benefits if exceeded that amount. In clinical settings, this serves as an observance that pharmacological therapies have their limitations in patient deliverance. 

Similarly, the drug deliverance also depends on detailed patient situations. The regulation of levodopa is different per each patient that takes it since their bodies respond differently, due to factors related to age and other health ailments. This is evident in clinical scenarios as, “Clinicians should discontinue the medication in patients that experience excessive daytime sleepiness. Long-term use of levodopa presents with other complications. The quality of life of patients can be negatively affected because of irreversible motor function changes from drug use” {4}. Looking at this particular information, levodopa has severe limitations on different individuals based on past medical histories, making it difficult to gauge a universal optimal amount of medical usage.

Looking at this problem pathologically, cells begin to undergo apoptosis (cell death) with the formation of “free radicals” {3}. With this process, regular healthy cells are marked for degeneration when levodopa enters the body. Because of this debilitating issue, clinicians should double-check all patient histories and ensure that levodopa will be used correctly within the body.

 

Conclusion

With the advent of levodopa and complementary medications such as carbidopa, treatments for Parkinson’s Disease are plentiful and portray a great deal of research. Levodopa is one of the most advanced treatments for aiding patients in all stages of Parkinson’s disease. Its pharmacological properties such as the central conversion to dopamine after crossing the blood-brain barrier are key in reversing symptoms of the disease. However, as levodopa has its downsides, other approaches such as carbidopa and dopamine agonists (promoters) can be used either to complement levodopa or to act as a substitute. Symptoms such as nausea, vomiting and dyskinesia were mentioned with the use of raw levodopa, thus clinicians can pair this up especially with carbidopa {3}. In conclusion, levodopa is one of the key therapies advancing the fight against Parkinson’s disease and is instrumental in slowing its progression. To potentially counter its downsides and ensure maximum potential, the medication should be deliberated by clinicians based on the disease stage that the patient presents with as well as the patient’s medical history.


References


  1. Rizek, P., Kumar, N., & Jog, M. (01/11/2016). An update on the diagnosis and treatment of Parkinson disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088077/. Retrieved: 01/07/2020.

  2. Annals of Indian Academy of Neurology. (n.d.). http://www.annalsofian.org/showstats.asp?issn=0972-2327;year=2017;volume=20;issue=3;month=July-September. Retrieved: 01/07/2020.

  3. Hinz, M., Stein, A., & Cole, T. (14/11/2014). Parkinson's disease: Carbidopa, nausea, and dyskinesia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4238750/. Retrieved: 01/07/2020.

  4. Poewe, W., Antonini, A., Zijlmans, J., Burkhard, P., & Vingerhoets, F. (07/09/2010). Levodopa in the treatment of Parkinson's disease: An old drug still going strong. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938030/. Retrieved: 01/07/2020.

  5. Gandhi, K. (23/04/2020). Levodopa (L-Dopa). https://www.ncbi.nlm.nih.gov/books/NBK482140/. Retrieved: 01/07/2020.

  6. Simon, W., & By, W. (n.d.). Levodopa. from https://scienceofparkinsons.com/tag/levodopa/.  Levodopa. Retrieved: 02/07/2020.

  7. “Stages of Parkinson's.” Parkinson's Foundation. https://www.parkinson.org/Understanding-Parkinsons/What-is-Parkinsons/Stages-of-Parkinsons. Retrieved: 27/07/2020.

  8. “What Is Parkinson's Disease.” Parkinson's Nebraska. https://parkinsonsnebraska.org/understanding-parkinsons-disease/. Retrieved: 02/08/2020.

Bibek Samal

Bibek Samal


Bibek Samal is a student at William B. Travis High School in Richmond, TX, and is enthusiastic about learning more about neuroscience. He loves sharing information about neurodegenerative diseases and surgical approaches to different disorders. He relaxes by hanging with his friends, watching Netflix, and playing varsity tennis for his school.