Table 2 Therapy With Compounds Of Disease
| Compound |
|---|
| Oertel et al. 2016100Quik et al. 2008101Hong et al. 2009102 |
Modified from Oertel and Schulz17 .
The second approach relates to the groundbreaking genetic discoveries in PD. In fact, a dramatic shift in the strategy for developing a new PD therapy has taken place: pharmaceutical efforts now target alpha-synuclein protein synthesis, degradation , protein aggregation, and propagation in the nervous system. Finally, 20 years after the discovery of PARK1, the academic and pharmaceutical industrial scientific community can offer the first candidates with a potential for a disease-modifying effect in PD.
Three different principles of therapeutic action are addressed: active or passive immunotherapy, modulation of alpha-synuclein aggregation, and enhancement of autophagy of alpha-synuclein .
Drug Delivery Systems For Neurotrophic Factor Therapy
Besides GDNF, other neurotrophic factor such as basic fibroblast growth factor have been evaluated. One example involves gelatin nanostructured lipid carriers encapsulating bFGF that can be targeted to the brain via nasal administration . Overall, the nanoformulation stimulated dopaminergic function in surviving synapses and played a neuroprotective role in 6-OHDA hemiparkinsonian rats. A very recent study took advantage of the neuroprotective properties of Activin B, which was administered in a parkinsonian mice using a thermosensitive injectable HG . The biomaterial allowed a sustained protein release over 5 weeks and contributed to substantial cellular protection and behavioral improvement.
What Will A Cure For Parkinson’s Look Like
Parkinson’s varies so much from person to person. There are over 40 symptoms of Parkinsons. Tremor. Pain. Hallucinations. Everyones experience is different.
Because of this, there may not be a single ‘cure’.
Instead we may need a range of different therapies to meet the needs of the individual and their specific form of the condition.
This mix may include treatments, therapies and strategies that can:
- slow or stop the progression of the condition
- replace or repair lost or damaged brain cells
- control and manage particular symptoms
- diagnose Parkinson’s at the earliest possible stage.
And this could involve medical treatments, such as drugs and surgical approaches, as well as lifestyle changes, for example to diet and exercise.
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Editorial Note On The Review Process
F1000 Faculty Reviews are commissioned from members of the prestigiousF1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions .
The referees who approved this article are:
-
Fredric P. Manfredsson, Parkinson’s Disease Research Unit, Department of Neurobiology, Barrow Neurological Institute, Phoenix, Arizona, USA
No competing interests were disclosed.
-
Tipu Z. Aziz, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
No competing interests were disclosed.
How Were Speeding Up The Search For A Cure
We believe that new and better treatments are possible in years, not decades, and we have a clear strategy for making this happen. This includes:
- backing the best and brightest minds to unlock scientific discoveries that will lead to new treatments and a cure
- accelerating the development and testing of new treatments through our Virtual Biotech
- collaborating internationally to make clinical trials faster, cheaper and more likely to succeed through the Critical Path for Parkinsons
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The Challenge Of Treating Motor And Non
In summary, neurologists, and especially movement disorder experts, can choose from a large number of compounds to treat the motor symptoms in PD effectively for several years, if not decades. In addition, owing to advances in the field of internal medicine, the surgical disciplines, and anesthesia, patients with PD live longer, but with a price or rather trade off to find the optimal therapeutic balance between motor- and non-motor symptoms with a minimum of adverse effects:
1) With increasing age and duration of PD, gait problemsnon-responsive to dopamimetic therapy, combined with the increased risk to fall and to incur fracturesand other NMSs appear. These NMSs include autonomic dysfunctions , sleep impairment, pain syndromes, and most important, neuropsychiatric symptoms, including depression, impulse control disorders, punding, hallucinations, overt psychosis , and cognitive impairment progressing to dementia. The NMSs substantially impair the quality of life not only of the PD-patient but also of their family. Thus, in the very advanced stages, the family and the physician facein many casesa disoriented, often demented PD patient, who either is mobile, if not hypermobile , and may hallucinate and even endanger him- or herself or others or who is akinetic-rigid.
Updates On Currently Approved Pd Treatments
Table 1 Approved dopaminergic drugs
Later, DA receptor agonists, such as those shown in Table , were developed either as monotherapies or combination therapies with L-DOPA for the treatment of PD. Five types of DA receptors, D1D5, exist in the brain. The D1 and D5 receptors are grouped together as D1-like receptors based on their stimulatory effects on adenylyl cyclase , and the D2, D3, and D4 receptors are classified as D2-like receptors due to their inhibition of cAMP activity. Many synthetic DA agonists, including pramipexole and apomorphine, activate D2-like receptors, and have a lower incidence of motor fluctuations and dyskinesia .
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Common Scale Of Motor Symptom Severity May Have Flaws: Study
A commonly used measure of how motor symptoms are affecting daily life could also for people in early stages of Parkinsons disease be taking into account the contribution of their non-motor symptoms, a study suggests. This is a likely reason for the discrepancies seen in evaluations made by patients
What Kinds Of Genetic Research Is Being Done
Researchers are investigating genes that code proteins responsible for producing dopamine. By increasing the amount of dopamine in the brain, Parkinsons symptoms can be minimized if not prevented.
What other treatments are being researched?
- Drug treatments. Researchers are investigating drugs that block the action of glutamate, an amino acid that destroys nerve cells, as well as the role of the antioxidant coenzyme Q-10 in slowing the progression of Parkinsons disease.
- Neural growth factor. Preliminary studies have shown that neural growth factor revives the dormant cells needed to produce dopamine, dramatically improving symptoms.
- Deep brain stimulation. Research is underway to better understand how deep brain stimulation works in Parkinsons disease. Researchers are also studying improved ways of stimulating the brain.
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The Shift From Research On Symptomatic Therapy To The Search For Parkinsons Disease
Based on these findings, the majority of cases with PD were assumed to present an alpha-synucleinopathy. Drug development shifted its focus from transmitters, transmitter-related receptor agonists and antagonists, and transmitter-synthesizing and -degrading enzymes to the protein chemistry, synthesis, transport, aggregation, and degradation of alpha-synuclein and other proteins related to neurodegenerative disorders, such as MAP-Tau or beta-amyloid. A now-20-year-long effort in neuroscience and drug development appears to provide the first results.
This article summarizes the recent achievements to further improve symptomatic therapy of motor PD symptoms, the still-limited attempts to provide symptomatic therapy for NMSs in PD, and the advances in the development and clinical testing of compounds, which promise to offer disease modification in already-manifest PD. However, prevention is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials, which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder , the most specific prodromal stage of PD – a methodological challenge to be met in the future.
New Technologies For The Diagnosis Clinical Assessment And Treatment Of Parkinsons Disease
In the last decade, new technology-based tools and technology-based therapies have been advanced with the objective of refining the diagnosis, clinical assessment and treatment of patients with movement disorders. The development and intricacy of molecular and cellular techniques, as well as extraordinary progress in technology, have marked a milestone in our general understanding of the disease.
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New Developments In Symptomatic Therapy Of Non
In summary, these compounds and techniques allow fine tuning of the available symptomatic therapy of motor and in part of NMSs in PD. However, they do not represent a major innovation. A true, highly needed innovation would be a compound with disease-modifying properties in order to slow down, if not stop, the progressive pathophysiology of PD .
What We Know So Far
- We’ve uncovered clues to the causes and genetic involvement in Parkinson’s.
- We’re figuring out the chain of events that leads to the damage and loss of brain cells.
- We’re working to advance new treatments and therapies.
- We’re exploring repurposing drugs to help manage some of the more distressing symptoms, like hallucinations and falls.
- And we know that, although people with Parkinson’s share symptoms, each person’s experience of the condition and response to treatment is different.
Now, the science is ready for us to develop the new treatments and cure that people with Parkinson’s so desperately need.
Research takes time but if you have Parkinsons, you need better treatments now. Thats why weve launched the Parkinson’s Virtual Biotech to speed up the most promising potential treatments. The more we can invest, the sooner we’ll get there.
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New Developments In Parkinsons Disease Therapy
With this situation in mind, efforts over the last 20 years to develop new therapies for PD can be divided in two categories: improving symptomatic therapy of motor and non-motor symptoms and addressing potential causes of PD, with a focus on the protein alpha-synuclein, its chemistry, synthesis, aggregation, degradation, and interaction with other proteins in order to develop a disease modifying treatment.
Recent Advances In The Preclinical Study Of Dopaminergic Drugs For Pd
Based on the multiple pathogenesis of PD, multifunctional agents may be good alternative options for PD treatment . Unfortunately, no such agents are available in the clinic. Table summarizes the chemical structures and binding or agonistic activity of preclinical dopaminergics.
Table 4 Polypharmacological dopaminergics for preclinical PD treatment
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Figure 1 Scheme Of A Dopaminergic Synapse With The Different Sites Of Actions For Symptomatic Parkinsons Disease Therapy
COMT, catechol-O-methyl-transferase D1, D1 receptor: agonist D2, D2/D3 receptor D2b, presynaptic D2-autoreceptor DDC, L-DOPA-decarboxylase DOPAC, dihydroxyphenylacetic acid L-DOPAa, L-dihydroxyphenylalanine MAO-A, monoaminooxidase A MAO-B, monoaminooxidase B TH, tyrosine hydroxylase 3MT, 3 methoxy-tyramine *, effect of L-DOPA **, effect of dopamine agonists ***, effect of MAO-B-inhibitor ****, effect of COMT-inhibitor , vesicle the round structure represents the symbol for the vesicle , the arrow represents the uptake mechanism dopamine reuptake mechanism. aRecently approved for therapy of Parkinsons disease .
Recent Advances In The Management Of Parkinson Disease
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The Decades Of Focus On The Nigrostriatal System And Dopamine Replacement Therapy
Parkinsons disease is a devastating disorder of the human nervous system and the second most common progressive chronic neurodegenerative disease. The three cardinal motor symptoms, akinesia in combination with either tremor at rest or rigidity , are200 years after their descriptionstill the basis of the clinical diagnosis. Up to 2016, we still have no treatment to slow down or even stop the progression of the disease. Available therapy is symptomatic. This article presents evidence that for the first time in history substances with a potentially disease-modifying effect for PD are under development and thus offer hope for the patient, the spouse, and the treating physician.
Multifunctional Agents With D2/d3 Receptor Agonist Antioxidant Or Iron Chelating Activities
Compared with ropinirole, D512 exhibits superior peak-dose efficacy and longer duration effects in improving the rotational activity in the 6-OHDA-induced unilaterally lesioned rat model despite having similar side effects, including drug-induced dyskinesia. In addition, D512 protects dopaminergic MN9D cells from MPP+- and 6-OHDA-induced toxicity, inhibits lipid peroxidation and caspase 3/7 activity, and rescues 6-OHDA-induced changes in nuclear morphology. Moreover, D512 protects rat adrenal pheochromocytoma PC12 cells from 6-OHDA-induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of PD. Furthermore, D512 displays neuroprotective effects against oxidative insult produced by buthionine sulfoximine, an inhibitor of glutathione synthesis, and 6-OHDA in PC12 cells.
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Mitochondrial Dysfunction And Oxidative Stress Related Biomarkers
Urate
Protein DJ-1
Additionally, Lin et al. have showed that the level of blood DJ-1 modified by 4-hydroxy-2-nonenal is significantly decreased in late-stage PD patients, suggesting that 4-HNE modified DJ-1 may potentially be one of the biomarkers of disease severity in the body fluid. The oxidized DJ-1 is promising to be a useful biomarker .
Coenzyme Q10
Homocysteine
8-Hydroxydeoxyguanosine
Advanced Oxidized Protein Products
Advanced oxidized protein products is a reliable biomarker of halogenative stress, and protein halogenation is a kind of oxidative stress induced by phagocytic overstimulation. When quantifying AOPP concentrations with enzyme-linked immunosorbent assays , researchers find that AOPP levels in serum of PD patients are significantly higher than control subjects. But there is no significant difference in CSF AOPP levels, because basal CSF levels are very low in all individuals. In addition, it has been demonstrated that the higher the Hoehn-Yahr stage or levodopa dose in PD patients or the longer the disease duration, the lower the serum AOPP levels . So AOPP will play an important role in diagnosis of PD and monitoring disease progression.
The Braak Staging Of Parkinsons Disease The Spreading Hypothesis The Search For Prodromal Stages Of Parkinsons Disease: Advantages And Limitations
Shortly after the discovery that a mutation of alpha-synuclein causes PD, alpha-synuclein aggregates were identified in the Lewy bodies in the post-mortem SN samples of patients with idiopathic PD. Therefore, the majority of patients with idiopathic PD are now considered to suffer from an alpha-synucleinopathy. Based on the distribution of these Lewy bodies in the nervous system, Braaket al. postulated that most likely PDas it is defined with its motor symptoms by the neurologistis a late-stage phenotype of a disease which has been going on for decades.
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Strategies For The Treatment Of Parkinsons Disease: Beyond Dopamine
- 1Laboratorio de NeurobiologÃa, Facultad de Ciencias de la Salud, Universidad San Sebastián, Concepción, Chile
- 2Department of Biological Sciences, University of Limerick, Limerick, Ireland
- 3Health Research Institute, University of Limerick, Limerick, Ireland
- 4Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO, United States
- 5Research & Development Service, Bay Pines VA Healthcare System, Bay Pines, FL, United States
Parkinsons disease is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal -synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.
Herbal Formulation With Anti
Ban Xia Hou Po Tang can significantly improve the swallowing reflex in Parkinson’s disease patients . Bushen Yanggan Xifeng Decoction has effects on neurotransmitters and DA receptors in the striatum of PD model mice . Chuanxiong Chatiao pelvis has neuroprotective effects against MPTP-induced dopaminergic neurotoxicity in mice models of Parkinson’s disease. Huanglian Jiedu Decoction has protective effects on the injury of PC12 cells induced by MPP+ . Kami-shojo-san has effects against tremors due to antipsychotic-induced PD . Liuwei Dihuang Pill can protect dopaminergic neurons in MPTP-induced PD mice . San-Huang-Xie-Xin-Tang has neuroprotective effects in the MPP+/MPTP models of PD in vitro and in vivo . Tianma Gauteng Yin has protective effects against apoptosis of dopaminergic neurons and oxidation stress response in Parkinson’s disease model rats . Yeoldahansotang has neuroprotective effects on the PD model via autophagy enhancement . Zhen-wu-tang has ameliorative and neuroprotective effects on rats induced by MPTP through keeping DA stable and vesicular monoamine transporter 2/DA transporter mRNA in balance . Zeichen Soup has the effect of promoting neural stem cell differentiation in PD model rats .
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