Advances in Parkinson’s Disease Drugs

Parkinson’s disease (PD) is the second most common neurodegenerative age-related disorder worldwide after Alzheimer’s disease [1–3], in which environmental and genetic factors play a pivotal role. PD is characterized by a dopamine deficiency due to dopaminergic neuronal death in the substantia nigra pars compacta, and Lewy bodies’ formation, containing alpha-synuclein and ubiquitin [4]. 

Click to cistanche tubulosa capsules for Parkinson's disease

Dystonia, bradykinesia, rigidity, resting tremor, and muscle cramps are the most reported motor symptoms in PD patients. Moreover, non-motor symptoms, such as mood and sleep disorders, apathy, depression, and cognitive dysfunctions are also described [5]. To date, although PD does not have a resolutive treatment, many efforts have been made in the field of drug discovery and delivery to investigate potential useful therapies to mitigate symptoms and provide short-term relief [6]. 

Levodopa (LD) is considered the most effective available drug to treat the motor symptoms of PD. However, additional medications such as monoamine oxidase B inhibitors, amantadine, anticholinergics, βblockers, or dopamine agonists, are commonly used [7]. In this Special Issue, five contributions, including four reviews and an original research article, were collected, to highlight the latest findings in terms of innovative therapeutic strategies or potential approaches to implementing scientific knowledge in the field of neurodegenerative disorders. 

All the collected papers underline the importance of investing in research regarding the development of novel drugs to improve the clinical framework of PD. The role of dopaminergic and non-dopaminergic agents was extensively reviewed by De Bello et al. [8]. 

The investigation focuses on recent receptor ligands that are useful in extending LD response and reducing undesired side effects. Following the same research line, Carrarini and co-workers [9], beyond summarizing the main PD pharmacological treatments that are suitable in each clinical stage of the disease and provide non-pharmacological treatment-supporting methods. They also emphasized the need to investigate biomarkers and prodromal symptoms for PD progression. 

A transversal approach has been examined by Ciulla et al. [10]. They screened the role of food supplements or functional food based on natural compounds, phytochemicals, vitamins, and minerals for their ability to postpone or alleviate the clinical symptoms of PD. These natural and plant-derived compounds laid the foundation for novel therapeutic approaches. 

Indeed, most of the examined compounds revealed antioxidant and anti-inflammatory properties, which are essential for counteracting oxidative stress and inducing dopaminergic neurons’ neuroprotection.

Further contributions consider therapeutic strategies to reduce oxidative stress and metal dyshomeostasis, conditions that are commonly correlated with PD. Tosato et al. [11] report a list of 800 compounds involved in the management of PD. 

Among the investigated entities, 250 compounds were considered for their possible metal-chelating properties towards ions that were extensively involved in the loss of metal homeostasis balance in PD. Moreover, Di Stefano et al. describe novel sulfur- and silent-L-Dopa derivatives named SP1–6 [12]. 

Among the investigated compounds, SP6 revealed significant antioxidant and protective activities, counteracting the neurotoxic effect of 6-hydroxydopamine and H2O2 in a RA/PMA-differentiated SY-SH5Y neuroblastoma cell line. SP6’s biological activity could be correlated to its ability to restore selenium deficiency, which is responsible for lower cognitive ability and reduced motor functions in PD patients.

How does Cistanche prevent Parkinson's disease?

Cistanche is a medicinal herb that has been traditionally used in China to improve brain function and prevent neurodegenerative diseases like Parkinson's disease. It is believed that the bioactive compounds found in Cistanche such as echinacoside, acteoside, and cistanosides have antioxidant, anti-inflammatory, and neuroprotective properties that help to prevent the death of dopaminergic neurons in the brain. 

Dopaminergic neurons are responsible for the production of dopamine, a neurotransmitter that is crucial for controlling movement and mood. The loss of dopamine-producing neurons is a key feature of Parkinson's disease. By protecting and preserving these neurons, Cistanche may help to prevent or slow the progression of Parkinson's disease. However, more scientific research is needed to confirm this potential benefit of Cistanche for Parkinson's disease.

References 

1Bologna, M.; Truong, D.; Jankovic, J. The etiopathogenetic and pathophysiological spectrum of parkinsonism. J. Neurol. Sci. 2021, 120012. [CrossRef] [PubMed] 

2. Laserra, S.; Basit, A.; Sozio, P.; Marinelli, L.; Fornasari, E.; Cacciatore, I.; Ciulla, M.; Türkez, H.; Geyikoglu, F.; Di Stefano, A. Solid lipid nanoparticles loaded with lipoyl–memantine codrug: Preparation and characterization. Int. J. Pharm. 2015, 485, 183–191. [CrossRef] [PubMed] 

3. Armstrong, M.J.; Okun, M.S. Diagnosis and treatment of Parkinson's disease: A review. JAMA 2020, 323, 548–560. [CrossRef] [PubMed] 

4. Miller, K.M.; Mercado, N.M.; Sortwell, C.E. Synucleinopathy-associated pathogenesis in Parkinson’s disease and the potential for brain-derived neurotrophic factor. NPJ Park. Dis. 2021, 7, 35. [CrossRef] [PubMed] 

5. Aarsland, D.; Batzu, L.; Halliday, G.M.; Geurtsen, G.J.; Ballard, C.; Chaudhuri, K.R.; Weintraub, D. Parkinson disease-associated cognitive impairment. Nat. Rev. Dis. Primers 2021, 7, 47. [CrossRef] [PubMed] 

6. Cacciatore, I.; Ciulla, M.; Marinelli, L.; Eusepi, P.; DI Stefano, A. Advances in prodrug design for Parkinson’s disease. Expert Opin. Drug Discov. 2018, 13, 295–305. [CrossRef] [PubMed] 

7. Charvin, D.; Medori, R.; Hauser, R.A.; Rascol, O. Therapeutic strategies for Parkinson's disease: Beyond dopaminergic drugs. Nat. Rev. Drug Discov. 2018, 17, 804–822. [CrossRef] 8. Del Bello, F.; Giannella, M.; Giorgioni, G.; Piergentili, A.; Quaglia, W. Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson’s Disease. Biomolecules 2019, 9, 142. [CrossRef] [PubMed] 

9. Carrarini, C.; Russo, M.; Dono, F.; Di Pietro, M.; Rispoli, M.G.; Di Stefano, V.; Ferri, L.; Barbone, F.; Vitale, M.; Thomas, A.; et al. A Stage-Based Approach to Therapy in Parkinson’s Disease. Biomolecules 2019, 9, 388. [CrossRef] [PubMed] 

10. Ciulla, M.; Marinelli, L.; Cacciatore, I.; Di Stefano, A. Role of Dietary Supplements in the Management of Parkinson’s Disease. Biomolecules 2019, 9, 271. [CrossRef] [PubMed] 

11. Tosato, M.; Di Marco, V. Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs. Biomolecules 2019, 9, 269. [CrossRef] [PubMed] 

12. Di Stefano, A.; Marinelli, L.; Eusepi, P.; Ciulla, M.; Fuller, S.; Di Filippo, E.S.; Magliulo, L.; Di Biase, G.; Cacciatore, I. Synthesis and Biological Evaluation of Novel Selenyl and Sulfur-l-Dopa Derivatives as Potential Anti-Parkinson’s Disease Agents. Biomolecules 2019, 9, 239. [CrossRef] [PubMed]

Antonio Di Stefano * and Lisa Marinelli

Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy