Parkinson’s Disease (PD) is characterized by a constant loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) region of the brain. Dehay et al. (2015) suggest that the formation of Lewy Bodies (LBs) is another pathological hallmark which correlates with PD and is associated with the non-physiological aggregation and misfolding of the protein α-synuclein, indicating that PD belongs to synucleopathies. The above pathological features are the precursors for the existence of significantly complicated motor and non-motor symptoms and, as a result, indicate the difficulties that have to be overcome when developing new, potential antiparkinsonian therapeutic approaches.
Dauer and Przedborski (2003) report that motor symptoms in PD comprise several kinetic impairments such as bradykinesia, tremor and rigidity, while Schapira and Chaudhuri (2009) report that non-motor symptoms are associated with several behavioral and psychological features of the patient including depression, anxiety, cognitive dysfunction etc.
Levodopa, the traditional therapeutic candidate for the treatment of PD, has been found to be surprisingly beneficial during the first stages of its administration but, unfortunately, that is not always the case when the disease progresses. Dauer and Przedborski (2003) mention that when administered continuously in a consistent therapy, levodopa itself may be the precursor for additional motor implications such as dyskinesia and even non-motor symptoms. Olanow, Obeso and Stocchi (2006) report that in most severe cases levodopa administration could potentially lead to a condition known as diphasic dyskinesia.
Many approaches suggest that replacing levodopa with another potential therapeutic alternative is of vital importance and new medicinal and pharmaceutical studies are being introduced. However, an approach of a different and quite interesting perspective suggests that there is already a therapy providing some relief on the patients. Therefore, along with the development of new drugs, research should also focus on the improvement of the already existed one, levodopa.
Barros, Ribeiro and Esteso (2019) mention that levodopa experiences some issues associated with its low water solubility. Barros et al. indicate, therefore, that several compounds could be combined with levodopa in order to improve its physicochemical properties, and the most novel candidates are known as cyclodextrins. Specifically, β-Cyclodextrin and Hydroxyalkalated-β-Cyclodextrin could potentially improve the pharmacodynamics and pharmacokinetics of L-Dopa and meanwhile decrease its toxicity. Using particular physicochemical concepts as well as thermodynamic models, the negative characteristics of a drug can be reversed to positive ones.
Different therapies are continuously being approached and all of them are essential in increasing our understanding of PD treatment. Two recent researches provided an interesting way of developing new compounds and techniques in the treatment of PD.
Gao et al. (2019) report that Gold Nanoclusters (AuNCs) consist of hundreds of ultra-small Gold Nanoparticles (AuNPs) and in the study they were combined with L-Isobutyryl-L-Cysteine (L-NIBC). Gao et al. (2019) report the magnificent biological compatibility and their facilitative interaction with biological systems as well as their unique chemical and physical properties were some of the reasons beyond the utilization of these remarkable particles in bioimaging and drug delivery. Gold nanoclusters were found to inhibit α-synuclein aggregation, to provide neuronal protection against MPP+ (1-Methyl-4-Phenylpyridine) neuronal toxicity as well as to improve the psychological implication caused by MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine. The study of course utilized in vitro, cell and mouse models and although it provided a very promising and hopeful approach, the case in humans could be quite different and additional studies have to be completed in order to have a more detailed view of these remarkable gold particles.
Another team of researchers used specific compounds called Clovamide analogues and tried to determine the importance of catechol, a characteristic functional group involved in treating PD. Feng et al. (2019) suggest that some Clovamide analogues were constructed with catechol groups and were the ones that induced several relief symptoms in model cells against oxidative stress and some Clovamide analogues were constructed without the catechol groups and had very low efficacy. These results indicated that Clovamide analogues with catechol groups could be a very promising therapeutic approach in the treatment of PD and in fact the most promising of them all was N-[3’,4’-Dihydroxy-(E)-Cinnamoyl]-Phenylalanine Methyl Ester.
Two different approaches include the use of endocannabinoid molecules (arachidonoyl glycerol – 2AG as well as arachidonoyl ethanol amide -anandamide) and ketone bodies. Baul & Sen (2019) report the importance of cannabinoid molecules in Parkinson’s Disease mainly through the effects of the Cannabinoid Receptor 2 (CB2R) which is found to alter its quantity in PD. Wlodarek (2019) mentions the role of ketone bodies mediated by the effects of the biomolecule β-hydroxybutyrate.
The complications of Parkinson’s Disease, however, also comprise a plethora of non-motor symptoms, which, unlike the motor impairments, are more difficult to diagnose and simultaneously correlated with the existence of PD. In many cases it had been found that some of the patients suffering from PD were embarrassed to visit a physician due to several conditions such as sexual dysfunction and loss of sex drive [Non-motor… patho].
A high number of PD patients develop serious behavioural and psychological manifestations such as depression. Schapira and Chaudhuri (2009) maintain that depression in PD has been partly associated with dysfunctions that also promote the existence of motor, kinetic implications, such as dopaminergic loss. Therefore, a therapeutic approach contains the use of pramipexole, which is a dopaminergic agonist, along with pergolide to provide an anti-depressant activity in PD patients (Schapira & Chaudhuri, 2009). Other antidepressants include drugs such as ropinirole, bupropion or sertraline (Schapira and Chaudhuri, 2009).
A very common feeling that develops in many cases of PD is associated with anxiety. In the case of PD, the developed anxiety is essentially more severe than the anxiety from which many people around us suffer in their everyday lives. In PD, the anxiety might be expressed as a fear of the individual to interact with his or her social cycle, which could potentially lead to the social isolation of the individual as a result. In even more severe cases of anxiety, the individuals might suffer from an extremely non-productive agent correlated with psychological importance, panic attacks. Dopaminergic therapy has been reported beneficial in the context of treating anxiety symptoms and providing anxiety relief in patients with PD, but dopaminergic therapy cannot constitute an absolute approach and does not efficiently work in many PD patients (Schapira and Chaudhuri, 2009).
As it was already mentioned, non-motor symptoms are difficult to be determined and therefore a lot of innovation is also required in the treatment of behavioural disorders associated with PD. A group of Korean scientists started a research in which the activities of an herbal medicine, known as yokukansan, were studied. Jang et al. (2018) mention in their study, that yokukansan is used as an agent that helps young children to fall asleep while in some more extreme cases it can also contribute to the improvement of hallucinations which might arise as a result of several psychological or even psychiatric situations including for instance insomnia or other sleep malfunctions. In symptoms resembling those of PD yokukansankachimpihange (yokukansan with the addition of a couple of more ingredients) was found to improve the time and the quality of sleep.
Other considerations are also significant for the efficient treatment of PD symptoms, both motor and non-motor. Polymeropoulos et al. (1998) indicate that our brain, for instance, consists of a very adequate percentage of the protein UCH-L1, suggested to be associated with Lewy Body formation. By obtaining additional knowledge of that proteolytic in nature protein, it would be possible to analyse more extensively the molecular basis of Lewy Body formation. Other considerations such as the development of the disease symptoms, the time required for levodopa to be efficacious and potent as well as the sex and environmental factors are all important (Jenner, 2015). Amongst the considerations, Xicoy, Wieringa and Martens (2019) mention that lipid metabolism malfunctions could potentially facilitate the progression of the pathological characteristics of Parkinson’s Disease as lipids form a crucial part of a cell’s and subsequently an organ’s proper function. Also, Tomlinson et al. (2010) report that by the dose equivalency of several therapies of levodopa it could be possible to have a theoretical view of the progression of the treatment in PD.