Phosphodiesterase 10 Inhibitors: New Disease Modifying Drugs for Parkinson’s Disease?

2014 ◽  
Vol 21 (10) ◽  
pp. 1171-1187 ◽  
Author(s):  
A.M. Garcia ◽  
M. Redondo ◽  
A. Martinez ◽  
C. Gil
2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S16-S17
Author(s):  
Connie Marras ◽  
Laura C Maclagan ◽  
Yi Cheng ◽  
Naomi Visanji ◽  
Mina Tadrous ◽  
...  

Abstract Given the high cost of drug development and low success rates, repurposing drugs already proven safe provides a promising avenue for identifying effective therapies with additional indications. The IBM Watson artificial intelligence system was used to search 1.3 million Medline abstracts to prioritize medications that may be potentially disease-modifying in Parkinson’s disease. We assessed patterns of use of the top 50 Watson-ranked drugs among 14,866 adults with Parkinson’s disease aged 70 and older who were matched to persons without Parkinson’s disease on age, sex, and comorbidity. Sociodemographic characteristics, chronic conditions, and use of other medications were compared using standardized differences. Patterns of potentially disease-modifying drug use were examined prior to and following ascertainment of Parkinson’s disease. Preliminary findings from multivariable conditional logistic regression models on the association between previous exposure to potentially disease-modifying drugs and Parkinson’s disease diagnosis will be presented.


2008 ◽  
Vol 84 (1) ◽  
pp. 25-39 ◽  
Author(s):  
Hervé Allain ◽  
Danièle Bentué-Ferrer ◽  
Yvette Akwa

2020 ◽  
Vol 21 (19) ◽  
pp. 7113
Author(s):  
Georgia Kouroupi ◽  
Nasia Antoniou ◽  
Kanella Prodromidou ◽  
Era Taoufik ◽  
Rebecca Matsas

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by loss of striatal-projecting dopaminergic neurons of the ventral forebrain, resulting in motor and cognitive deficits. Despite extensive efforts in understanding PD pathogenesis, no disease-modifying drugs exist. Recent advances in cell reprogramming technologies have facilitated the generation of patient-derived models for sporadic or familial PD and the identification of early, potentially triggering, pathological phenotypes while they provide amenable systems for drug discovery. Emerging developments highlight the enhanced potential of using more sophisticated cellular systems, including neuronal and glial co-cultures as well as three-dimensional systems that better simulate the human pathophysiology. In combination with high-throughput high-content screening technologies, these approaches open new perspectives for the identification of disease-modifying compounds. In this review, we discuss current advances and the challenges ahead in the use of patient-derived induced pluripotent stem cells for drug discovery in PD. We address new concepts implicating non-neuronal cells in disease pathogenesis and highlight the necessity for functional assays, such as calcium imaging and multi-electrode array recordings, to predict drug efficacy. Finally, we argue that artificial intelligence technologies will be pivotal for analysis of the large and complex data sets obtained, becoming game-changers in the process of drug discovery.


Drugs ◽  
2015 ◽  
Vol 75 (18) ◽  
pp. 2065-2071 ◽  
Author(s):  
Ariane Park ◽  
Mark Stacy

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Rong Yin ◽  
Jie Xue ◽  
Yanfeng Tan ◽  
Chuantao Fang ◽  
Chunchun Hu ◽  
...  

Parkinson’s disease (PD) is a complex neurodegenerative disease, manifested by the progressive functional impairment of the midbrain nigral dopaminergic neurons. Due to the unclear underlying pathogenesis, disease-modifying drugs for PD remain elusive. In Asia, such as in China and India, herbal medicines have been used in the treatment of neurodegenerative disease for thousands of years, which recently attracted considerable attention because of the development of curative drugs for PD. In this review, we first summarized the pathogenic factors of PD including protein aggregation, mitochondrial dysfunction, ion accumulation, neuroinflammation, and oxidative stress, and the related recent advances. Secondly, we summarized 32 Chinese herbal medicines (belonging to 24 genera, such as Acanthopanax, Alpinia, and Astragalus), 22 Chinese traditional herbal formulations, and 3 Indian herbal medicines, of which the ethanol/water extraction or main bioactive compounds have been extensively investigated on PD models both in vitro and in vivo. We elaborately provided pictures of the representative herbs and the structural formula of the bioactive components (such as leutheroside B and astragaloside IV) of the herbal medicines. Also, we specified the potential targets of the bioactive compounds or extractions of herbs in view of the signaling pathways such as PI3K, NF-κB, and AMPK which are implicated in oxidative and inflammatory stress in neurons. We consider that this knowledge of herbal medicines or their bioactive components can be favorable for the development of disease-modifying drugs for PD.


BMJ Open ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. e047993
Author(s):  
Nirosen Vijiaratnam ◽  
Christine Girges ◽  
Grace Auld ◽  
Marisa Chau ◽  
Kate Maclagan ◽  
...  

IntroductionParkinson’s disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure.Methods and analysisThis is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks.The primary outcome is the comparison of Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences.Ethics and disseminationThis trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format.Trial registration numbersNCT04232969, ISRCTN14552789.


2020 ◽  
Vol 15 ◽  
pp. 117727192096407
Author(s):  
Lucia Farotti ◽  
Federico Paolini Paoletti ◽  
Simone Simoni ◽  
Lucilla Parnetti

Diagnosis of Parkinson’s disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer’s disease (AD) biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.


2020 ◽  
Vol 29 (8) ◽  
pp. 864-872
Author(s):  
Laura C. Maclagan ◽  
Naomi P. Visanji ◽  
Yi Cheng ◽  
Mina Tadrous ◽  
Alix M. B. Lacoste ◽  
...  

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Liang Song ◽  
Meng-Bei Xu ◽  
Xiao-Li Zhou ◽  
Dao-pei Zhang ◽  
Shu-ling Zhang ◽  
...  

To date, no drug has been proven to be neuroprotective or disease-modifying for Parkinson’s disease (PD) in clinical trials. Here, we aimed to assess preclinical evidence of Ginsenosides-Rg1 (G-Rg1), a potential neuroprotectant, for experimental PD and its possible mechanisms. Eligible studies were identified by searching six electronic databases from their inception to August 2016. Twenty-five eligible studies involving 516 animals were identified. The quality score of these studies ranged from 3 to 7. Compared with the control group, two out of the 12 studies of MPTP-induced PD showed significant effects of G-Rg1 for improving the rotarod test (P<0.01), two studies for improving the swim-score values (P<0.01), six studies for improving the level of TH protein expression (P<0.01), and two studies for increasing the expression of TH mRNA in the substantia nigra of mice (P<0.01). The studies reported that G-Rg1 exerted potential neuroprotective effects on PD model through different mechanisms as antineuroinflammatory activities (n=10), antioxidant stress (n=3), and antiapoptosis (n=11). In conclusion, G-Rg1 exerted potential neuroprotective functions against PD largely by antineuroinflammatory, antioxidative, and antiapoptotic effects. G-Rg1 as a promising neuroprotectant for PD needs further confirmation by clinical trials.


2015 ◽  
Vol 73 (7) ◽  
pp. 1365-1379 ◽  
Author(s):  
Dan Lindholm ◽  
Johanna Mäkelä ◽  
Valentina Di Liberto ◽  
Giuseppa Mudò ◽  
Natale Belluardo ◽  
...  

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