Treatments of Parkinson’s Disease

            Given that Parkinson’s was first characterized in 1817, a lot of the first treatments that were proposed in the 100 years following James Parkinson’s “An Essay on the Shaking Palsy” were not very effective. Regardless, Parkinson himself recognized that a cure needed to be found, and medical intervention would need to be implemented prior to the onset of severe motor dysfunction in order to maintain the well-being of the patient. Parkinson devised therapeutic strategies such as bloodletting from the neck, in an effort to divert blood and inflammation away from brain and spinal cord. Although this method did not yield great results, it was nonetheless an interesting plan based off of how little researchers knew about PD at the time.2

            Jean-Martin Charcot would later implement belladonna alkaloids as a treatment for Parkinson’s related tremor. This would be considered the first true PD treatment outside of Parkinson’s initial attempts. Surprisingly, this treatment was also relatively effective. Belladonna alkaloids are centrally active anticholinergic drugs, and are able to affect the cholinergic / dopaminergic balance within the substantia nigra and striatum of the brain.38Charcot would also investigate the efficacy of vibratory therapy, however the technology that was being used at the time was not nearly sophisticated enough to be more widely utilized.

            Beginning in the early 1900s, surgical intervention became a much more popular treatment option, despite the fact that the typical mortality rate of the various surgeries was around 10%. Despite the risks associated with the surgeries, this method of treatment was the most popular form throughout the 1900s up until the introduction of levodopa therapy. The most common surgical procedures used in an effort to treat PD included cerebral cortex excision, basal ganglia lesion, pallidotomy, sub thalamic nucleus ablation, among many, many others.39It would seem that from a surgical perspective, researchers left no stone unturned.4041

Reaction converting L-DOPA to dopamine by DOPA decarboxylase.
http://blog.hvmn.com/biohacker-guide/nootropics/l-dopa

            In the 1960s, levodopa therapy was introduced, and completely changed the landscape of Parkinson’s disease treatment. Anticholinergic drugs of the past were recognized as being somewhat effective, but having undesirable side effects. As a result, there was a need for a different drug that more effectively target the striatum. Dopamine was first synthesized in 1910, and the discovery of the enzyme dopa decarboxylase showed the method by which levodopa could be converted to dopamine. After the essential discovery in the 1950s of the localization of dopamine in the brain, specifically in the striatum, it soon became clear that a loss of dopamine in the brain coincided with Parkinson’s symptoms, and that the introduction of an outside source of dopamine could have the potential to treat, or even reverse PD symptoms.42Clinical trials were soon put into effect, and in 1969 George Cotzias published an article which indicated that in 28 patients with PD, levodopa treatment displayed modest improvement in 4 patients, moderate improvement in 4 patients, marked in 10, and dramatic in 10. Additionally, few side effects of this treatment were shown, and some side effects of the nervous system were actually welcomed, like an improvement in memory and a healthier outlook. Negative side effects of the treatment included nausea / vomiting, and anorexia. However, these side effects were likely due to activation of dopaminergic neurons of the vomiting centers; some of which are located outside of the blood brain barrier.42Because of the efficacy, and limited number of negative side effects of this treatment, levodopa therapy has remained one of the most popular therapeutic strategies, even after its implementation more than 50 years ago.

            Another popular form of treatment used today are dopamine agonists. Although DA agonists provide minimal improvement in terms of symptoms, they are actually believed to be less neuroteoxic than levodopa. Levodopa has displayed a “wearing off” effect, and is thus more often used after symptoms have progressed extremely far, and impact the daily lives of patients in a significant way. Thus, in patients whose symptoms are much milder, DA agonists could be the better method of treatments.43DA agonists are capable of treatment by directly activating dopamine receptors, bypassing the presynaptic synthesis of dopamine entirely. It is believed that DA agonists are most effective in mediating the anti-Parkinson’s effects by targeting the D2 receptor of the indirect movement pathway.43

            Another treatment option that is drastically different the previous few, is deep brain stimulation of the motor thalamus. This procedure built off of the surgical procedures of the past in order to create a much safer and more reliable invasive method of PD therapy. DBS is done by introducing metal wires within sections of the brain, and send electrical signals in an effort to control motor symptoms by regulating abnormal electrical signaling patterns. The wires are most often placed in the subthalamic nucleus for the most significant reduction of PD symptoms.44DBS is more effective in treating patients whose symptoms lean towards stiffness, slowness or tremor. This treatment is less effective at treating symptoms like postural imbalance. Outside of what symptoms are observed, other factors play into whether or not a patient is eligible for DBS, such as age, level of brain atrophy, and the presence of any sever psychiatric disorders.44

Figure demonstrating the placement of the wires within the brain during DBS treatment for PD.
https://www.ninds.nih.gov/About-NINDS/Impact/NINDS-Contributions-Approved-Therapies/DBS

            It is clear that many of these treatments only seem to be implanted to reduce symptoms of PD, rather than treating the underlying cause. This is obviously due to our lack of understanding of both the healthy state of alpha-synuclein, as well as the diseased state and process of aggregation and Lewy body formation. As our understanding of the biochemical mechanisms continue to expand, then the possibilities for novel therapeutic strategies will begin to take shape. Possibilities could include the activation and maintenance of the proteasome, to ensure that alpha-syn aggregates can be removed with the typical machinery responsible for this process. Or perhaps a method for misfolding prevention of alpha-syn could be elucidated, eliminating the need for other forms of PD treatment used now. The future of Parkinson’s disease is uncertain, but with the trajectory that current research is on, we could be closer to finding a cure for PD than we think.

References

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5 replies on “Treatments of Parkinson’s Disease”

There’s a lot of growing research searching for more subtle pharmacological treatment options, such as the use of positive allosteric modulators. These can provide a boost in signaling while still maintaining the temporal aspects of the neuronal inputs/outputs. Can you please provide any updates on the future of these options?

Excellent question. Within the past couple of years, researchers have identified numerous positive allosteric modulator candidates for the neurotransmitter receptor mGlu4. The hope for these drug candidates is that they will be able to assist motor symptoms in both early and late stages. Many of these candidates, including VU2957 (Valiglurax) have shown a great deal of promise in studies both in vitro and in vivo, and soon clinical trials will determine whether or not PAMs are the treatment of the future for Parkinson’s disease.

Oh, and many patients have to cycle through many different drug treatments, from very effective to mildly effective options. Could you elaborate on this?

Hey Matt, nice job! I have a question about levodopa therapies. I understand that L-DOPA can be converted to dopamine through the action of DOPA decarboxylase, but why exactly is this step necessary? If the loss of dopamine is a reason for Parkinson’s symptoms then why are patients not just given dopamine? I imagine that introducing dopamine to the body has a large variety of negative effects or just cannot make it to the brain. If this is the reason why they do not use dopamine directly, could you explain how dopamine causes these effects, and if not, can you explain why they use L-DOPA instead of dopamine?

Hey Alex, great question! What is interesting about L-DOPA treatment, and the whole process that is involved, is that dopamine is not capable of crossing the blood brain barrier. As a result, a different form of dopamine was required to cross it, and L-DOPA was the best candidate. Once L-DOPA is able to cross the blood brain barrier, it is converted to dopamine, as you pointed out, by DOPA decarboxylase, and can then fill in for the lost dopamine.

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