Extracellular Vesicles in the Treatment of Parkinson’s Disease: A Review

2021 ◽  
Vol 28 ◽  
Author(s):  
Xiaoxiao Yang ◽  
Yifan Ma ◽  
Haotian Xie ◽  
Shiyan Dong ◽  
Gaofeng Rao ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Extracellular Vesicles ◽  
Dopamine Agonists ◽  
Motor Symptoms ◽  
Nonmotor Symptoms ◽  
Isolation And Characterization ◽  
Organ Systems ◽  
Delivery Platform

Background: Parkinson’s disease (PD) is one of the most common neurological disorders that can severely affect the ability to perform daily activities. The clinical presentation of PD includes motor and nonmotor symptoms. The motor symptoms generally involve movement conditions like tremors, rigidity, slowness, and impaired balance. In contrast, the nonmotor symptoms are often not apparent but can affect various organ systems, such as the urinary and gastrointestinal systems, and mental health. Gene mutations and toxic environmental factors have contributed significantly to PD; nevertheless, its cause and underlying mechanism remain unknown. Currently, treatments such as dopamine agonists, RNA molecules, and antioxidants can, to some extent, alleviate the motor symptoms triggered by PD. However, these medicines cannot effectively halt ongoing dopaminergic damage, mainly because the blood-brain barrier (BBB) lowers the efficiency of drug delivery. Recently, extracellular vesicles (EVs), a novel drug delivery platform, have been widely used in various neurological diseases, including stroke and brain tumors, because of their excellent biocompatibility, their ability to penetrate the BBB without toxicity, and their target specificity. EVs thus provide a promising therapeutic for treating PD. Objective: This review focuses on novel therapies based on EVs in practice. Herein, we briefly introduce the biogenesis, composition, isolation, and characterization of EVs, and we discuss strategies for loading therapeutic agents onto EVs and recent applications for PD treatment. Moreover, we discuss perspectives on the direction of preclinical and clinical studies regarding novel and effective therapies. Methods: A literature search regarding PD treatment based on extracellular vesicles was performed in PubMed (updated in June 2020). Treatment, therapy, drug delivery, extracellular vesicles, and their combinations were the search queries. Both systematic reviews and original publications were included. Searched results were selected and compared based on relevance. Articles published in the last five years were given top priority. Conclusion: PD is a heterogeneous disease that can be treated by using pharmacologic approaches (e.g., dopamine agonists and levodopa) and nonpharmacologic approaches (e.g., music), based on symptoms and progression level in patients. Even though current treatments have demonstrated effectiveness, clinical challenges remain because the BBB reduces medication received and lowers the efficacy of drug delivery, which impairs the treatment’s effect. Therefore, EVs, as an emerging delivery platform, are highly promising for PD treatment since they can readily cross the BBB with high therapeutic efficiency through the loading or functionalization process. However, defining a safe source of EVs, reliably purifying and isolating EVs with high yield, and improving the efficacy of therapeutic loading in EVs remain challenging in this field. Therefore, future investigations should focus on generating large-scale exosomal carriers and designing new effective drugs encapsulated in EVs for better efficacy.

scholarly journals Genetic Impact on Clinical Features in Parkinson’s Disease: A Study on SNCA-rs11931074

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Li Shu ◽  
Dongxiao Liang ◽  
Hongxu Pan ◽  
Qian Xu ◽  
Jifeng Guo ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Features ◽  
Rating Scale ◽  
Motor Symptoms ◽  
Nonmotor Symptoms ◽  
Association Analyses ◽  
Comorbidity Burden ◽  
Severe Motor ◽  
Genetic Impact

SNCA-rs11931074 had been demonstrated to be strongly correlated with PD risk. However, there was lack of comprehensive analysis of SNCA-rs11931074-related clinical features which may help explain clinical heterogeneity of PD. In our study, we performed association analyses on the relationship between SNCA-rs11931074 and motor symptoms, nonmotor symptoms, and comorbidities in PD. 611 rs11931074 carriers and 113 rs11931074 noncarriers were enrolled. In the clinical phenotype analyses, the Unified Parkinson’s Disease Rating Scale part II (UPDRS II) and part III (UPDRS III) scores of rs11931074 carriers were lower than those of noncarriers (SC: −0.083, p=0.035; SC: −0.140, p≤0.001). The Charlson Comorbidity Index (CCI) score of carriers was lower than that of noncarriers (SC: −0.097, p=0.009). No significant statistical differences were found between the variant and other clinical features such as motor complications and nonmotor symptoms. The SNCA-rs11931074 carriers may present with more benign clinical profiles than noncarriers with less severe motor symptoms and comorbidity burden.

scholarly journals Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

2020 ◽  
Author(s):  
Valerie Joers ◽  
Gunasingh Masilamoni ◽  
Doty Kempf ◽  
Alison R Weiss ◽  
Travis Rotterman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sex Differences ◽  
Microglial Activation ◽  
Motor Deficits ◽  
Sexually Dimorphic ◽  
Motor Symptoms ◽  
Tnf Inhibitor ◽  
Nonmotor Symptoms ◽  
Monkey Model

AbstractInflammation has been linked to the development of nonmotor symptoms in Parkinson’s disease (PD), which greatly impact patients’ quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a “gold standard” model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

scholarly journals Characterization of Nonmotor Symptoms in the MitoPark Mouse Model of Parkinson’s Disease

2020 ◽  
Author(s):  
Monica R. Langley ◽  
Shivani Ghaisas ◽  
Bharathi N. Palanisamy ◽  
Muhammet Ay ◽  
Huajun Jin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Antidepressant Treatment ◽  
Forced Swim Test ◽  
Cognitive Learning ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Nonmotor Symptoms ◽  
Forced Swim ◽  
Non Motor Symptoms

AbstractMitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinson’s disease (PD). The MitoPark mouse, a transgenic mitochondrial impairment model developed by specific inactivation of TFAM in dopaminergic neurons, spontaneously exhibits progressive motor deficits and neurodegeneration, recapitulating several features of PD. Since non-motor symptoms are now recognized as important features of the prodromal stage of PD, we monitored the clinically relevant motor and nonmotor symptoms from ages 8-24 wks in MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wks and became severe by 16-24 wks. Interestingly, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wks and becoming most severe at 16 wks, as determined by Morris water maze. When compared to age-matched control mice, MitoPark mice exhibited olfactory deficits in novel and social scent tests as early as 10-12 wks. MitoPark mice between 16-24 wks spent more time immobile in forced swim and tail suspension tests, and made fewer entries into open arms of the elevated plus maze, indicating a depressive and anxiety-like phenotype, respectively. Importantly, depressive behavior as determined by immobility in forced swim test was reversible by antidepressant treatment with desipramine. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in cognitive learning and memory, olfactory discrimination, and anxiety-and depression-like behaviors. Thus, MitoPark mice can serve as an invaluable model for studying motor and non-motor symptoms in addition to studying pathology in PD.

scholarly journals Co-loading of Levodopa and Curcumin Using Brain-targeted Protocells as a Drug Delivery System for Improving the Efficacy of Parkinson's Disease

2020 ◽  
Author(s):  
wenkai zhou ◽  
Chang Liu ◽  
Feifei Yu ◽  
Xia Niu ◽  
Xiaomei Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Inner Core ◽  
Cell Model ◽  
Mesoporous Silica Nanoparticles ◽  
Brain Targeting ◽  
Delivery Platform ◽  
A Cell

Abstract Parkinson's disease (PD), one of the most common movement and neurodegenerative disorders, is challenging to treat, partly because the blood-brain barrier blocks passage of most drugs. Levodopa is a common clinical drug for controlling the symptoms of PD, but it only replenishes the missing dopamine, can’t protect dopaminergic neurons. While curcumin as a neuroprotective agent has been reported for treatment of PD. Herein, we present a novel organic-inorganic composite nanoparticle with brain targeting (denoted as lf-protocells) for co-delivery of levodopa and curcumin, and demonstrate its attractive use as a biocompatible platform for PD treatment. The nanoparticle system is comprised of a lactoferrin (lf) modified lipid bilayer (LB) containing curcumin as its outer membrane and mesoporous silica nanoparticles (MSNs) containing levodopa as its supporting inner core. Our studies illustrate that the lf-protocells have a size of about 180 nm and spherical morphology, and can be used to co-load levodopa and curcumin efficiently. Further, a cell model and a mouse model induced by rotenone (Rot) and MPTP respectively are used to investigate the effects of binary-drug loaded lf-protocells on PD. Our results demonstrate that the combination of curcumin and levodopa alleviate the apoptosis of PD cells, enhance the cell viability as compared to levodopa used alone; levodopa together with curcumin also efficiently decrease the expression of a-synuclein, increase the expression of tyrosine hydroxylase in SH-SY5Y cells, and transform more levodopa into dopamine for supplement the loss of the brain. Moreover, the resulting binary-drug loaded lf-protocells ameliorate oxidative stress and mitochondrial dysfunction as compared to combination of free drugs. In addition, testing in a mouse model indicate that lf-protocells can improve significantly the motor function and distribution in brain compared with unmodified protocells. In conclusion, binary-drug loaded lf-protocells show much better therapeutic efficacy in both the cell model and the mouse model of PD and lower toxicity than bare MSNs. These results suggest that lf-protocells can be used as a promising drug delivery platform for targeted therapy against PD and other diseases of the central nervous system.

scholarly journals Parkinson’s Disease-Related Motor and Nonmotor Symptoms in the Lancaster Amish

2020 ◽  
Vol 54 (5) ◽  
pp. 392-397
Author(s):  
Michael D.F. Goldenberg ◽  
Xuemei Huang ◽  
Honglei Chen ◽  
Lan Kong ◽  
Teodor T. Postolache ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Daytime Sleepiness ◽  
Bowel Movement ◽  
Motor Symptoms ◽  
Nonmotor Symptoms ◽  
Case Identification ◽  
Movement Frequency ◽  
Bowel Movements ◽  
Bowel Movement Frequency

<b><i>Introduction:</i></b> Previous research has suggested that the Amish may experience a relatively high prevalence of Parkinson’s disease (PD) and/or parkinsonian motor signs. <b><i>Methods:</i></b> In a large sample from the Amish community in Lancaster County, Pennsylvania, age ≥18 years, we assessed the prevalence of self-reported PD diagnosis. For those without self-reported PD diagnosis, we assessed the frequency of PD-related motor symptoms using a 9-item questionnaire that was designed by the PD Epidemiology Research Group. Lastly, we queried study participants for the presence of 2 nonmotor symptoms that have been commonly linked to PD: bowel movement frequency and daytime sleepiness. <b><i>Results:</i></b> Among 2,025 subjects who answered the PD questionnaire, 430 were older than 60 years. Of 430 participants ≥60 years, 5 (1.2%) reported a PD diagnosis. Of those without a PD diagnosis, 10.5% reported ≥1 and 1.2% ≥ 4 motor symptoms for the 9-item PD screening questionnaire. Of the 3,789 subjects who answered the question about bowel movement frequency, 0.7% reported ≤3 bowel movements per week. Among 1,710 subjects who answered the question about daytime sleepiness, 8.1% of the participants reported “always” sleepy during the day. <b><i>Discussion:</i></b> These data neither support a markedly higher PD prevalence in the older Lancaster Amish nor do they show dramatically higher motor and/or selected nonmotor symptoms than the general population. Future studies that employ more rigorous procedures for case identification and PD-specific preclinical symptoms/tests are needed to determine the potential differences and similarities among different Amish populations and between Amish and non-Amish populations.

scholarly journals Non-motor symptom burden in patients with Parkinson’s disease with impulse control disorders and compulsive behaviours: results from the COPPADIS cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
S. Jesús ◽  
◽  
M. A. Labrador-Espinosa ◽  
A. D. Adarmes ◽  
C. Méndel-Del Barrio ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Impulse Control ◽  
Dopamine Agonists ◽  
Rating Scale ◽  
Disease Onset ◽  
Impulse Control Disorders ◽  
Nonmotor Symptoms ◽  
Premorbid Personality ◽  
Validated Questionnaire

Abstract The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson’s disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose.

Extracellular Vesicles as Drug Delivery Vehicles for Potent Redox Enzyme Catalase to Treat Parkinson's Disease

2018 ◽  
Vol 128 ◽  
pp. S18 ◽  
Author(s):  
Matthew J. Haney ◽  
Natalia L. Klyachko ◽  
Yuling Zhao ◽  
Alexander V. Kabanov ◽  
Elena V. Batrakova
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Extracellular Vesicles ◽  
Redox Enzyme ◽  
Drug Delivery Vehicles ◽  
Delivery Vehicles

scholarly journals Neurocognitive Correlates of Apathy and Anxiety in Parkinson's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yelena Bogdanova ◽  
Alice Cronin-Golomb
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuropsychological Tests ◽  
Rating Scales ◽  
Disease Duration ◽  
Differential Association ◽  
Motor Symptoms ◽  
Healthy Controls ◽  
Nonmotor Symptoms ◽  
Neurocognitive Profiles

Parkinson's disease (PD) is associated with various nonmotor symptoms including neuropsychiatric and cognitive dysfunction. We examined the relation between apathy, anxiety, side of onset of motor symptoms, and cognition in PD. We hypothesized that PD patients would show different neuropsychiatric and neurocognitive profiles depending on the side of onset. 22 nondemented PD patients (11 right-side onset (RPD) with predominant left-hemisphere pathology, and 11 LPD) and 22 matched healthy controls (NC) were administered rating scales assessing apathy and anxiety, and a series of neuropsychological tests. PD patients showed a higher anxiety level than NC. There was a significant association between apathy, anxiety, and disease duration. In LPD, apathy but not anxiety was associated with performance on nonverbally mediated executive function and visuospatial measures, whereas, in RPD, anxiety but not apathy correlated with performance on verbally mediated tasks. Our findings demonstrated a differential association of apathy and anxiety to cognition in PD.

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