When it comes to Parkinson's disease, if we are only talking about “low dopamine levels”, then we are missing a very important part of the conversation:
dopamine levels are reduced in part because of the death and dysfunction of the cells that normally make dopamine in the body.
In Parkinson's disease, cells are affected in the substantia nigra, a part of the brain with lots of dopamine-producing cells (called dopaminergic neurons). However the disease also occurs in others parts of the brain, and even outside the brain, in cells of the body (1). In fact, as Schulz-Schaeffer argues, a lack of dopamine is a tertiary event. It occurs due to the death of the cells, which is still only a secondary event; and what we should be considering the primary event is synaptic dysfunction of still existing nerve cells (2). In other words, what science is suggesting occurs first is dysfunction at the junction between nerve cells (known as the synapse). This means that Parkinson's begins as a disease that affects and erodes the communication of nerve cells between one another (2).
Many different neurotransmitter systems that aren't dopamine are also affected. These include serotonin, noradrenaline and acetylcholine pathways (1, 3). In many cases, research suggests that it's not the dopamine pathways that are affected first, but some of these other pathways (1-3).
Therefore, we need to begin thinking of Parkinson's as more than just a disorder of low dopamine. Instead, we need to begin asking why are these cells, which should ordinarily be producing dopamine in the first place, getting sick and dysfunctional? And what can we do to improve their cellular health, and maintain the health of the ways in which they communicate with one another?
The main drugs used today to treat Parkinson’s are Levodopa (L-Dopa) and Carbidopa. L-Dopa is made in the brain and kidneys, and is a precursor to dopamine. In other words, it’s used by the body to create dopamine. However, we can also take it synthetically in the form of a drug. By taking L-Dopa medication, L-Dopa levels in the body are increased, which can be used by the brain to create more dopamine.
L-Dopa was developed in the '60s and was a huge development for Parkinson's (4). It continues to significantly help many people with their symptoms, offering better movement control so that they can continue getting on with life. It's still considered one of the first lines of treatment for someone with PD. At SYMBYX, we believe in a multi-faceted, collaborative approach to healthcare, and recognise the critical role medications play for improving peoples' health and wellbeing. Therefore we never recommend any changes to medication, and always suggest discussing any treatment changes with your consulting physician.
Yet it's important to recognise that, like most therapies, L-Dopa medication may also have some negative side effects for some people. Because L-Dopa is taken via the gut (either ingested in the form of a pill, or slow-released via a dopamine pump), it causes an increase in L-Dopa around the body, not just the brain (remember, dopamine is used by cells around the entire body). An increase in dopamine outside the brain can cause your blood vessels to dilate (contributing to common side effects of light-headedness, headache and dizziness), your kidneys to produce more sodium so you urinate more (leading to increased dehydration and dry mouth symptoms), and your gut motility to slow down so that you lose your appetite and get nauseous. Ironically, this can exacerbate constipation, a common PD symptom, which, in turn, can further affect L-Dopa absorption (5).
Because of these common side effects, L-Dopa is often prescribed with carbidopa. Carbidopa inhibits L-Dopa breakdown before it reaches the brain. This can help reduce side effects, by reducing the amount of L-Dopa synthesised into dopamine in the gut or periphery, and further improves the efficacy of L-Dopa. Unfortunately, even with Carbidopa, it’s suggested that < 10% of L-Dopa reaches the brain unchanged (6).
L-Dopa and dopamine supplementation is certainly very helpful. However it's still a symptom management tool. Our cells are capable of producing dopamine, however in Parkinson's disease, they are becoming sick and dysfunctional. By shifting the conversation away from just talking about "low dopamine", and beginning to talk about "cellular health", we may move closer towards better understanding the process of the disease, and can also begin to talk about optimising health, not just about treating illness.
The mechanisms of Parkinson's disease is likely due to a combination of factors. Current scientific hypotheses include:
1) mitochondrial dysfunction;
2) ion channelopathy;
3) alpha-synuclein aggregation causing neuroinflammation;
4) excessive oxidative stress;
5) an unhealthy gut microbiome;
6) impaired cellular autophagy; and
7) nigral iron accumulation (interestingly, there is a 'chicken or egg' discussion as to whether the accumulation of iron in the brain is due to PD medications, as opposed to being a true effect of the disease (7)).
Therapies such as light therapy work with the body’s natural healing processes to improve the functioning of cells. Specifically, light therapy is showing promise to be able to:
1) improve mitochondrial function;
2) stimulate ion channels;
3) reduce neuroinflammation;
4) reduce oxidative stress;
5) improve the gut microbiome; and
6) regulate cellular autophagy (8-13).
And that’s just the tip of the iceberg!
This is why light therapy is so promising as a treatment modality for Parkinson's. It can help reduce the stress and inflammation of our cells and optimise their ability to heal and function by working with the body's natural processes. The net result is better cellular health, in the body and in the brain. And the net result of that includes more dopamine!
References:
1) Lim SFox SHLang AE. Overview of the Extranigral Aspects of Parkinson Disease. Arch Neurol. 2009;66(2):167–172. doi:10.1001/archneurol.2008.561
2) Schulz-Schaeffer WJ. Is Cell Death Primary or Secondary in the Pathophysiology of Idiopathic Parkinson's Disease? Biomolecules. 2015 Jul 16;5(3):1467-79. doi: 10.3390/biom5031467. PMID: 26193328; PMCID: PMC4598759.
3) Braak H, Del Tredici K, Rüb Ude Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24 (2) 197- 211
4) Ovallath S, Sulthana B. Levodopa: History and Therapeutic Applications. Ann Indian Acad Neurol. 2017 Jul-Sep;20(3):185-189. doi: 10.4103/aian.AIAN_241_17. PMID: 28904446; PMCID: PMC5586109.
5) Xu J, Wang L, Chen X, Le W. New Understanding on the Pathophysiology and Treatment of Constipation in Parkinson's Disease. Front Aging Neurosci. 2022 Jun 22;14:917499. doi: 10.3389/fnagi.2022.917499. PMID: 35813960; PMCID: PMC9257174.
6) Mannisto PT, Kaakkola S: New selective COMT inhibitors: useful adjuncts for Parkinson’s disease? Trends Pharmacol Sci 1989;10:54–56.
7) Du G, Wang E, Sica C, Chen H, De Jesus S, Lewis MM, Kong L, Connor J, Mailman RB, Huang X. Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage. Mov Disord. 2022 Aug;37(8):1654-1662. doi: 10.1002/mds.29062. Epub 2022 May 25. PMID: 35614551; PMCID: PMC9810258.
8) Hamblin MR. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys. 2017;4(3):337-361.
9) Salehpour F, Sadigh-Eteghad S, Mahmoudi J, Kamari F, Cassano P, Hamblin MR (2023). Photobiomodulation for the Brain: Photobiomodulation Therapy in Neurology and Neuropsychiatry. Springer Charm. https://doi.org/10.1007/978-3-031-36231-6.
10) Dompe C, Moncrieff L, Matys J, Grzech-Leśniak K, Kocherova I, Bryja A, Bruska M, Dominiak M, Mozdziak P, Skiba THI, Shibli JA, Angelova Volponi A, Kempisty B, Dyszkiewicz-Konwińska M. Photobiomodulation-Underlying Mechanism and Clinical Applications. J Clin Med. 2020 Jun 3;9(6):1724. doi: 10.3390/jcm9061724. PMID: 32503238; PMCID: PMC7356229.
11) Bicknell B, Liebert A, McLachlan CS, Kiat H. Microbiome Changes in Humans with Parkinson's Disease after Photobiomodulation Therapy: A Retrospective Study. J Pers Med. 2022 Jan 5;12(1):49. doi: 10.3390/jpm12010049. PMID: 35055364; PMCID: PMC8778696.
12) Liebert A, Capon W, Pang V, Vila D, Bicknell B, McLachlan C, Kiat H. Photophysical Mechanisms of Photobiomodulation Therapy as Precision Medicine. Biomedicines. 2023 Jan 17;11(2):237. doi: 10.3390/biomedicines11020237. PMID: 36830774; PMCID: PMC9953702.
13) Pevna V, Horvath D, Wagnieres G, Huntosova V. Photobiomodulation and photodynamic therapy-induced switching of autophagy and apoptosis in human dermal fibroblasts. J Photochem Photobiol B. 2022 Sep;234:112539. doi: 10.1016/j.jphotobiol.2022.112539. Epub 2022 Aug 8. PMID: 35973285.
