Neurodegenerative diseases account for a significant and increasing proportion of morbidity and mortality in today’s scenario. It affects millions of people worldwide [1]. Alzheimer’s and Parkinson’s disease are the most common among all known neurodegenerative diseases, Occurrence of neurodegenerative dementias and neurodegenerative movement disorders are more prevalent in the modern-day population. These diseases are one of the most important medical and socio-economic problems of our time, affecting a wide range of aged people, resulting in a major impact at professional, social, and family levels of patients and can lead to a complete inability to carry out various type of everyday activity. It has been estimated that 46.8 million individuals were affected with Dementia in 2017. This number is expected to be achieving 75 million in 2030 and 131.5 million by 2050 [2]. As the population ages, neurodegenerative diseases, such as Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's disease (PD), and Huntington's disease, pose an increasingly greater threat and related consequences to human health and also piling burden on the health‐care system [3]. Significant advances regarding the molecular aspects of these diseases have not yet been translated into real improvements in therapeutics. In this regard, neurodegenerative diseases are highly complex and involve critical molecular events governing the establishment and progression of each disease. Moreover, molecular changes actively trigger pathophysiological cascades involving the immune response, oxidative stress, and mitochondrial dysfunction, among others, ultimately leading to neuronal impairment and subsequently death [4]. Similarly, these alterations also affect glial cells and brain vasculature, which contribute directly to the progression of these disorders. Currently there is no established cure for degenerative diseases, but we have several symptomatic treatments. There are some common medicines for these diseases, such as dopaminergic treatments for PD and movement disorders, cholinesterase inhibitors for cognitive disorders, antipsychotic drugs for behavioural and psychological symptoms of dementia, analgesic drugs for pain, anti-inflammatories for infections, and even the use of deep brain stimulation to stop tremor andrefractory movement disorders [5]. In the current scenario, various therapeutic drug approaches have been proposed to treat the symptoms of neurodegenerative diseases. Yet there exists a void for effective drug therapies.

Causes of Neurodegenerative Disorders

Neurodegenerative disorders, which are chronic and progressive, are recognized by selective and symmetric loss of neurons in motor, sensory, or cognitive systems. Characterization of the patterns of cell loss and the identification of disease-specific cellular markers have aided in nosologic classification [6]. The causative factors differ in different neurodegenerative disorders. In the case of Alzheimer’s disease, three hypotheses are proposed which are the cholinergic hypothesis, Amyloid hypothesis, and Tau hypothesis. According to the cholinergic hypothesis, Alzheimer's disease is caused by poor synthesis of acetylcholine, which is an essential neurotransmitter. While Amyloid hypothesis states that deposition of β-Amyloid proteins ultimately forms plaques around neurons leading to their dysfunction and finally degeneration. Another hypothesis that is Tau hypothesis proposes that active deposition of Tau protein form tangles within neurons or brain cells [7].

Another most common neurodegenerative disease is Parkinson’s disease. The mechanism involved in the development of PD includes various factors like the aggregations of misfolded proteins, activation of protein degradation pathways, mitochondrial damage, and oxidative stress, along with certain gene mutations [8]. Aggregation of misfolded proteins includes the accumulation of Lewy bodies in dopamine neurons of the substantia nigra pars compacta. Protein degradation pathways Ubiquitin-proteasome system (UPS) is chiefly responsible for the degradation of misfolded or damaged proteins in the cytosol, nucleus, or endoplasmic reticulum (ER). Impairment in this system leads to the aggregation of misfolded amyloid proteins (Lewy bodies). Chaperones (heat shock proteins/HSP) undergo dysfunctioning, as they play a vital role in the cell-defense mechanism involved in protein degradation and folding of proteins. Major HSPs involved are HSP 26, HSP40, HSP 60, HSP 70, HSP 90, and HSP 100. HSPs aggregate with α-synuclein and form insoluble structures resulting in reduced toxicity of α-synuclein [9].

Huntington's disease (HD) is also a rare neurodegenerative disease of the central nervous system which is characterized by unwanted choreatic movements, behavioural and psychiatric disturbances, and dementia. It has been reported that Mutant huntingtin results in neuronal dysfunction and death through several mechanisms. These include direct effects from the exon 1 mHTT fragment, the propensity of mHTT to form abnormal aggregates, and its effects on cellular proteostasis, axonal transport, transcription, and translation [10]. The aggregation of huntingtin is exacerbated through the disease‐related impairment of the proteostasis network, which also leads to global cellular impairments. The aberrant forms of huntingtin result in additional global cellular impairments, including synaptic dysfunction, mitochondrial toxicity, and a decreased rate of axonal transport [11].

Factors Associated with Neurodegenerative Diseases

The factors which are strongly associated with neurodegenerative diseases are aberrant protein dynamics with aggregation and degradation of defective protein, oxidative stress and reactive oxygen species (ROS) formation, impaired bioenergetics, and mitochondrial dysfunction, and excessive exposure to metals and pesticides (Figure 1). Misfolding and aggregation are recognized as common molecular events for a large number of human diseases due to improper trafficking, premature degradation, or the appearance of toxic folds. Deposition and aggregation of such defective proteins have been observed in the brain tissues of the patients affected by these disorders [12].

Loss of mitochondrial function is strongly associated with an increase in the generation of reactive oxygen intermediates and several human diseases, thus alterations in mitochondrial dynamics potentially increase ROS, mtDNA damage, and the loss of energy production which are important contributors that assist in the pathophysiology associated with several neurodegenerative diseases. [13].

Pesticides encompass an array of synthetic compounds that are designed to kill insects and pests [14]. Some work has been done by the researchers to investigate the hypothesis that exposure to pesticides could be related to central nervous system disorders several studies have shown a positive association between pesticide exposure and the development of severe neurodegenerative diseases [15].

Molecular Signalling Linked with Neurodegenerative Diseases

Signalling pathways play a key role in the regulation and maintenance of the structure and function of the adult brain. It is found that the activity of signalling pathways viz. Wnt is present in the following areas of the brain: frontal cortex, cerebellum, hippocampal, basal forebrain, and olfactory bulb. Damage or dysfunction of neurons in these areas can lead to various neurodegenerative disorders. 

Wnt signaling plays a crucial role in synaptic stability as well as in the maintenance of blood-brain barrier integrity [16]. Malfunctioning of the Wnt/β-catenin signaling cascade has been strongly associated with Alzheimer's disease onset and development. 

Figure1: Factors associated with neurodegenerative diseases 

Figure 2: Molecular mechanism proposed for the Wnt/β-catenin deregulation in Alzheimer’s and Parkinson’s disease

Presenilins (PS1) is found to be involved in the modulation of the Wnt canonical pathway. Under normal conditions, PS1 inhibits GSK-3β activity, enhancing β-catenin stability, by stimulating Akt. Conversely, PS1 mutations in Alzheimer’s disease patients are associated with increased GSK3β levels and low β catenin levels, which result in the inactivation of the Wnt/β-catenin pathway [17] (Figure 2). Studies suggested that dysfunction or loss of the Wnt canonical pathway is implicated in Alzheimer’s disease pathogenesis, while the activation of the Wnt canonical pathway offsets Alzheimer’s disease pathology by protecting neurons against Aβ-toxicity, by reducing synapse loss and ameliorating cognitive performances [18].

Several studies have suggested a link between Parkinson’s disease pathogenesis and the Wnt canonical pathway. Sancho et al., [19] reported that under normal conditions, LRRK2 interacts with the members of the Wnt family, specifically with the dishevelled proteins (Dvl-1, Dvl-2, and Dvl-3). LRKK2 acts as a scaffold protein, which connects both membrane and cytosolic components of the Wnt canonical pathway, such as the intracellular domain of LRP6 with the Dvl proteins. Dvl proteins with the components of the β-catenin destruction complex, promoting and enhancing the activation of the Wnt canonical pathway [20]. Instead, LRRK2 mutations in Roc, COR, and kinase domains, can reduce the LRRK2-LRP6 binding affinity and have been associated with reduced activation of the Wnt canonical pathway and increased neurodegeneration. To probe a putative link between LRKK2 and GSK-3β, the expression of the mutant LRRK2 protein (G2019S) was induced in Drosophila, concluding that mutant LRRK2 possesses the ability to recruit GSK-3β. In turn, GSK-3β phosphorylates the Tau protein thus aggravating neurodegeneration [21].

According to the proposed role of the Wnt canonical pathway in Huntington’s disease pathogenesis, mutated Huntingtin protein (mHtt) interferes with β-catenin turnover. Huntingtin protein (Htt) acts as a scaffold protein that plays a role in promoting β-catenin phosphorylation by the β-catenin destruction complex. On the other hand, mat interferes with β-catenin degradation by binding with some members of the β-catenin destruction complex and thus leading to its toxic stabilization in the cytoplasm [22]. Current findings indicate that the downregulation of the Wnt signaling pathway in Huntington’s disease correlates with decreased transcription of Wnt pro-survival genes and therefore, with increased apoptosis. Further studies are requested to evaluate other molecular mechanisms eventually involving the Wnt/β-catenin signalling in this disease.

Calcium Signalling in Neurodegenerative Diseases

Calcium (Ca2+) is an essential ubiquitous second messenger that regulates various activities in cells.

Neurons require extremely precise spatial-temporal control of calcium-dependent processes because they regulate such vital functions as synaptic plasticity [23].

Calcium signalling and Alzheimer’s disease

One potential connection between Alzheimer’s disease pathogenesis and Ca2+ comes from the observation that Aβ oligomers can form Ca2+ permeable channels in membranes. It has been observed that exposure of phosphatidylserine (PtdS) on the cell surface is an indication that the cell is in an energy deficit condition which further enhances the ability of Aβ to associate with the membrane [24]. The increased local concentration of Aβ oligomers in the area surrounding amyloid plaques leads to the formation of Ca2+-permeable ion channels in the neuronal plasma membrane. The neurites with elevated Ca2+ levels lacked spines and displayed an abnormal morphology [25]. Studies suggested that exaggerated neuronal Ca²⁺ signals are due to the accumulation of Aβ oligomers or expression of FAD mutants in presenilins. A report suggests that mutation in a novel Ca²⁺-influx channel that is calcium homeostasis modulator 1 (CALHM1), might increase the risk of late-onset Alzheimer’s Disease [26].

Calcium Signalling in Parkinson’s Disease

α-synuclein is the chief element of Lewy bodies commonly found in the brains of Parkinson’s disease patients. The probable mechanism of α-synuclein toxicity is related to the formation of small α-synuclein aggregates (protofibrils). Biophysical studies showed that synucleinprotofibrils form ion pores in lipid membranes and induce Ca²⁺ influx in neurons [27]. SNc dopaminergic neurons use Ca_V1.3 L-type Ca²⁺ channels to initiate and drive spontaneous pacemaking activity. The continuous Ca²⁺ influx creates a heavy metabolic load on SNc neurons ultimately making them vulnerable to secondary stress on mitochondrial function. The reliance of SNc neurons on L-type Ca²⁺ channels to control pacemaking increases with age, which might be an explanation that age is such a significant risk factor for developing Parkinson’s disease [28]. 

Calcium Signalling in Huntington’s Disease

Huntington’s disease is a purely genetic disorder that is caused by a mutation in the huntingtin (Htt) gene [29]. The majority of researchers share the view that mutant Htt protein acquires a toxic gain of function [30]. Disruption of neuronal Ca²⁺ signalling is one of the toxic functions of the Htt protein. Steady changes in the expression level of many Ca²⁺ signalling proteins were observed in microarray studies of the brains of patients with Huntington’s disease.

Therapeutics and Treatment Strategies in Neurodegenerative Diseases

Although the treatment of neurodegenerative diseases remains a complex and challenging task, there are several effective drugs and therapeutic approaches that have been introduced for the treatment of these neurodegenerative diseases in modern society, but still, researchers are looking forward to finding more established treatments. At present, some common drugs have been suggested to treat the symptoms of neurodegenerative diseases (Table 1).

Amantadine hydrochloride has pharmacological actions as an anti-Parkinson drug [31]. The mechanism of action of Amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not well established but data from various studies suggest that Amantadine may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that Amantadine is a weak, non-competitive NMDA receptor antagonist (K1 = 10μM) which increases dopamine release and prevents dopamine reuptake.

Donepezil hydrochloride is an acetylcholinesterase inhibitor most commonly used for the treatment of Alzheimer's disease. Donepezil is FDA approved for use in mild, moderate, and severe Alzheimer's disease. There is no evidence that donepezil alters the progression of the disease. It can, however, ameliorate some symptoms by improving cognition and/or behavior. Donepezil hydrochloride is a piperidine derivative that binds reversibly to acetylcholinesterase and inhibits the hydrolysis of acetylcholine, thus increasing the availability of acetylcholine at the synapses, enhancing cholinergic  transmission. Some in vitro data has suggested that the anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain [32].

Table 1: Commonly used drugs in neurodegenerative diseases

Source- Access pharmacy

Levodopa is an active precursor of the neurotransmitter dopamine. It is most commonly used as a dopamine replacement agent for the treatment of Parkinson's disease. Unlike dopamine, levodopa can cross the blood-brain-barrier (BBB) [33]. Levodopa converts into dopamine in both the CNS and periphery. After being converted to dopamine, it activates postsynaptic dopaminergic receptors and compensates for the decrease in endogenous dopamine. Levodopa has been strongly suggested as a reasonable treatment option for patients with neurodegenerative disease. Recent studies have suggested that levodopa can efficiently slow down the progression of Parkinson's disease [34].

Ropinirole is an anon-ergoline dopamine agonist, with preferential affinity for the D2-like (D2, 3, 4) receptors. ropinirole has been approved to treat symptoms of early and advanced Parkinson’s disease, it has the highest affinity at the D3 receptors which are concentrated in the limbic areas of the brain immediate release has a long-established position in the management of Parkinson’s disease. Short duration studies in early Parkinson’s disease [35].

Pramipexole is an essential selective dopaminergic agonist with a minor agonistic activity at other receptors. According to the dissociation constant (Km in nmol/L), the lower the value, the higher affinity of a drug to a receptor. Pramipexole has been recorded to be having the lowest Km value with the D3 dopaminergic receptor and a slightly higher value for the D2 receptor. Thereby, it is highly specific to D3 and D2 receptors with affinity to D3 being about eight times higher than that to D2 [36]. It binds actively to presynaptic dopamine autoreceptors exerting negative feedback on endogenous dopamine synthesis. Ultimately this process leads to a decrease in oxidative stress, which is responsible for mitigates the damage on the nigrostriatal pathways [37].

Tetrabenazine, which is an active oral monoamine depleter, is a hexahydro-dimethoxy-benzoquinolizine derivative. Tetrabenazine found to act primarily as a reversible high-affinity inhibitor of monoamine uptake into granular vesicles of presynaptic neurons by binding selectively to Vesicular monoamine transporter (VMAT-2). Because of this inhibition, monoamine degradation in the neuron is augmented, which ultimately leads to the depletion of the monoamines, particularly dopamine. Various studies have shown that tetrabenazine also blocks dopamine D2 receptors, but this affinity is 1,000-fold lower than its affinity for VMAT-2 [38].

Neurodegenerative disorders are major medical and socio-economic problems of today’s world, affecting a wide range of aged people, resulting in a major impact at professional, social, and family levels of patients and acting as a hurdle for a better life expectancy. In the light of recent studies and researches in the field of neurodegenerative disorder, different types of neurodegenerative diseases seem to share some common causative factors such as mitochondrial damage, misfolding of proteins, chaperons malfunction, protein aggregates, and exposure to heavy metals and pesticides. Till today, there is no potent drug to completely cure or eradicate these disorders but there are several therapeutics and drugs to treat the symptoms and lessen the severity of the disease. We have tried to highlight the most common neurodegenerative disorders, their causative factors, and their suitable targeted drugs emphasizing their mode of action. Researches and studies to date suggest that there is a void of potent and effective drugs to combat these disorders. Moreover, researchers are potentially looking forward to finding out novel strategies to cope with this serious problem. The deteriorating ambient environment acting as a stimulus for the epigenetic changes must be studied deeply to chalk out its pathway, which later leads to mutation and malfunctioning of the specific proteins. There is a need to peep deeper into the proteomics and genomics of molecules associated with these disorders.

Acknowledgment

We would like to thank peers and colleagues who directly or indirectly helped us in this study. The authors deeply acknowledge Department of Zoology, Aligarh Muslim University and Department of Life Sciences, Mewar University for providing necessary facilities.

1. Zahra, W. et al. “The Global Economic Impact of Neurodegenerative Diseases: Opportunities and Challenges.” Bioeconomy for Sustainable Development, Springer Singapore, 2020, pp. 333–345. Springer Professional

2. McGill-Carter, T. 14th International Conference on Alzheimer’s Disease and Dementia. Conference proceedings, Barcelona, Spain, May 2020. (No reliable journal record located; entry formatted as a conference item from available conference listings). @WalshMedical

3. D’Souza, G.X. et al. “The Application of In Vitro-Derived Human Neurons in Neurodegenerative Disease Modeling.” Journal of Neuroscience Research, vol. 99, no. 1, 2020, pp. 124–140. https://doi.org/10.1002/jnr.24615. PMC+1

4. Reddy, P.H. “Role of Mitochondria in Neurodegenerative Diseases: Mitochondria as a Therapeutic Target in Alzheimer’s Disease.” CNS Spectrums, vol. 14, Suppl. 7, 2009, pp. 8–13. PMC+1

5. Chen, X., and W. Pan. “The Treatment Strategies for Neurodegenerative Diseases by Integrative Medicine.” Integrative Medicine International, vol. 1, no. 4, October 2015, pp. 223–225. https://doi.org/10.1159/000381546. Karger Publishers

6. Martin, J.B. “Molecular Basis of the Neurodegenerative Disorders.” New England Journal of Medicine, vol. 340, no. 25, 1999, pp. 1970–1980. https://doi.org/10.1056/NEJM199906243402507. PubMed

7. Lee, S.J. et al. “Protein Aggregate Spreading in Neurodegenerative Diseases: Problems and Perspectives.” Neuroscience Research, vol. 70, no. 4, Aug. 2011, pp. 339–48. https://doi.org/10.1016/j.neures.2011.05.008. PMC+1

8. Dauer, W., and S. Przedborski. “Parkinson’s Disease: Mechanisms and Models.” Neuron, vol. 39, no. 6, 11 Sept. 2003, pp. 889–909. https://doi.org/10.1016/S0896-6273(03)00568-3. PubMed+1

9. Karunanithi, S., and I.R. Brown. “Heat Shock Response and Homeostatic Plasticity.” Frontiers in Cellular Neuroscience, vol. 9, 2015, p. 68. Frontiers+1

10. Ross, C.A., and S.J. Tabrizi. “Huntington’s Disease: From Molecular Pathogenesis to Clinical Treatment.” The Lancet Neurology, vol. 10, no. 1, Jan. 2011, pp. 83–98. https://doi.org/10.1016/S1474-4422(10)70245-3. PubMed+1

11. Sari, Y. “Huntington’s Disease: From Mutant Huntingtin Protein to Neurotrophic Factor Therapy.” International Journal of Biomedical Science (IJBS), vol. 7, no. 2, 2011, p. 89. (Open-access copy available). PMC+1

12. Wood, J.D. et al. “Protein Aggregation in Motor Neurone Disorders.” Neuropathology and Applied Neurobiology, vol. 29, no. 6, Nov. 2003, pp. 529–545. PubMed+1

13. Van Houten, B. et al. “Role of Mitochondrial DNA in Toxic Responses to Oxidative Stress.” DNA Repair (Amst), vol. 5, no. 2, 3 Feb. 2006, pp. 145–152. https://doi.org/10.1016/j.dnarep.2005.03.002. PubMed+1

14. Baltazar, M.T. et al. “Pesticides Exposure as Etiological Factors of Parkinson’s Disease and Other Neurodegenerative Diseases — A Mechanistic Approach.” Toxicology Letters, vol. 230, no. 2, 2014, pp. 85–103. PubMed+1

15. Baldi, I. et al. “Neurodegenerative Diseases and Exposure to Pesticides in the Elderly.” American Journal of Epidemiology, vol. 157, no. 5, 2003, pp. 409–414. PubMed+1

16. Purro, S.A. et al. “Dysfunction of Wnt Signaling and Synaptic Disassembly in Neurodegenerative Diseases.” Journal of Molecular Cell Biology, vol. 6, no. 1, 2014, pp. 75–80. PubMed+1

17. Boonen, R.A.C.M. et al. “Wnt Signaling in Alzheimer’s Disease: Up or Down, That Is the Question.” Ageing Research Reviews, vol. 8, no. 2, Apr. 2009, pp. 71–82. PubMed

18. Libro, R. et al. “The Role of the Wnt Canonical Signaling in Neurodegenerative Diseases.” Life Sciences, vol. 158, 1 Aug. 2016, pp. 78–88. https://doi.org/10.1016/j.lfs.2016.06.024. PubMed+1

19. Sancho, R.M. et al. “Mutations in the LRRK2 Roc-COR Tandem Domain Link Parkinson’s Disease to Wnt Signalling Pathways.” Human Molecular Genetics, vol. 18, no. 20, 15 Oct. 2009, pp. 3955–3968. https://doi.org/10.1093/hmg/ddp337. PubMed+1

20. Berwick, D.C., and K. Harvey. “LRRK2 Functions as a Wnt Signaling Scaffold, Bridging Cytosolic Proteins and Membrane-Localized LRP6.” Human Molecular Genetics, vol. 21, no. 22, 2012, pp. 4966–4979. https://doi.org/10.1093/hmg/dds342. PubMed+1

21. Lin, C.H. et al. “LRRK2 G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3β.” Journal of Neuroscience, vol. 30, no. 39, 2010, pp. 13138–13149. PubMed+1

22. Godin, J.D. et al. “Mutant Huntingtin-Impaired Degradation of β-Catenin Causes Neurotoxicity in Huntington’s Disease.” The EMBO Journal, vol. 29, no. 14, 2010, pp. 2433–2445.

23. Pchitskaya, E. et al. “Calcium Signaling and Molecular Mechanisms Underlying Neurodegenerative Diseases.” Cell Calcium, vol. 70, 2018, pp. 87–94.

24. Lee, G. et al. “Annexin 5 and Apolipoprotein E2 Protect against Alzheimer’s Amyloid-β-Peptide Cytotoxicity by Competitive Inhibition at a Common Phosphatidylserine Interaction Site.” Peptides, vol. 23, no. 7, 2002, pp. 1249–1263.

25. Kuchibhotla, K.V. et al. “Aβ Plaques Lead to Aberrant Regulation of Calcium Homeostasis In Vivo Resulting in Structural and Functional Disruption of Neuronal Networks.” Neuron, vol. 59, no. 2, 2008, pp. 214–225.

26. Dreses-Werringloer, U. et al. “A Polymorphism in CALHM1 Influences Ca²⁺ Homeostasis, Aβ Levels, and Alzheimer’s Disease Risk.” Cell, vol. 133, no. 7, 2008, pp. 1149–1161.

27. Danzer, K.M. et al. “Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding.” Journal of Neuroscience, vol. 27, no. 34, 2007, pp. 9220–9232.

28. Chan, C.S. et al. “‘Rejuvenation’ Protects Neurons in Mouse Models of Parkinson’s Disease.” Nature, vol. 447, no. 7148, 2007, pp. 1081–1086.

29. Gusella, J.F., and M.E. MacDonald. “Molecular Genetics: Unmasking Polyglutamine Triggers in Neurodegenerative Disease.” Nature Reviews Neuroscience, vol. 1, no. 2, 2000, pp. 109–115.

30. Li, S., and X.J.Li. “Multiple Pathways Contribute to the Pathogenesis of Huntington Disease.” Molecular Neurodegeneration, vol. 1, no. 1, 2006, pp. 1–10.

31. Crosby, N.J. et al. “Amantadine for Dyskinesia in Parkinson’s Disease.” Cochrane Database of Systematic Reviews, no. 2, 2003.

32. Kumar, A., and S.Sharma. Donepezil. StatPearls, StatPearls Publishing, 2020.

33. Haddad, F. et al. “Dopamine and Levodopa Prodrugs for the Treatment of Parkinson’s Disease.” Molecules, vol. 23, no. 1, 2018, p. 40.

34. Gandhi, K.R., and A.Saadabadi. Levodopa (L-Dopa). StatPearls, StatPearls Publishing, 2019.

35. Shill, H.A., and M.Stacy. “Update on Ropinirole in the Treatment of Parkinson’s Disease.” Neuropsychiatric Disease and Treatment, vol. 5, 2009, p. 33.

36. Singh, R., and M.Parmar. Pramipexole. StatPearls, StatPearls Publishing, 2020.

37. Li, P.C. et al. “Time-Intensity-Based Volumetric Flow Measurements: An In Vitro Study.” Ultrasound in Medicine & Biology, vol. 28, no. 3, 2002, pp. 349–358.

38. Yero, T., and J.A.Rey. “Tetrabenazine (Xenazine), an FDA-Approved Treatment Option for Huntington’s Disease–Related Chorea.” Pharmacy and Therapeutics, vol. 33, no. 12, 2008, p. 690.

39.  

40.