Importance of Nanoparticles for the Delivery of Antiparkinsonian Drugs

Parkinson’s disease (PD) affects around ten million people worldwide and is considered the second most prevalent neurodegenerative disease after Alzheimer’s disease. In addition, there is a higher risk incidence in the elderly population. The main PD hallmarks include the loss of dopaminergic neurons and the development of Lewy bodies. Unfortunately, motor symptoms only start to appear when around 50–70% of dopaminergic neurons have already been lost. This particularly poses a huge challenge for early diagnosis and therapeutic effectiveness. Actually, pharmaceutical therapy is able to relief motor symptoms, but as the disease progresses motor complications and severe side-effects start to appear. In this review, we explore the research conducted so far in order to repurpose drugs for PD with the use of nanodelivery systems, alternative administration routes, and nanotheranostics. Overall, studies have demonstrated great potential for these nanosystems to target the brain, improve drug pharmacokinetic profile, and decrease side-effects.

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α-Synuclein in Parkinson’s Disease: Does a Prion-Like Mechanism of Propagation from Periphery to the Brain Play a Role?

The Neuroscientist ◽

10.1177/1073858420943180 ◽

2020 ◽

pp. 107385842094318

Author(s):

Huimin Zheng ◽

Changhe Shi ◽

Haiyang Luo ◽

Liyuan Fan ◽

Zhihua Yang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Cellular Level ◽

Motor Symptoms ◽

Lewy Neurites ◽

Growing Body ◽

Non Motor Symptoms ◽

The Brain

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, defined as motor and non-motor symptoms associated with the loss of dopaminergic neurons and a decreased release of dopamine (DA). Currently, PD patients are believed to have a neuropathological basis denoted by the presence of Lewy bodies (LBs) or Lewy neurites (LNs), which mostly comprise α-synuclein (α-syn) inclusions. Remarkably, there is a growing body of evidence indicating that the inclusions undergo template-directed aggregation and propagation via template-directed among the brain and peripheral organs, mainly in a prion-like manner. Interestingly, some studies reported that an integral loop was reminiscent of the mechanism of Parkinson’s disease, denoting that α-syn as prionoid was transmitted from the periphery to the brain via specific pathways. Also the systematic life cycle of α-syn in the cellular level is illustrated. In this review, we critically assess landmark evidence in the field of Parkinson’s disease with a focus on the genesis and prion-like propagation of the α-syn pathology. The anatomical and cell-to-cell evidences are discussed to depict the theory behind the propagation and transferred pathways. Furthermore, we highlight effective therapeutic perspectives and clinical trials targeting prion-like mechanisms. Major controversies surrounding this topic are also discussed.

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Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies

npj Vaccines ◽

10.1038/s41541-021-00424-2 ◽

2022 ◽

Vol 7 (1) ◽

Author(s):

Changyoun Kim ◽

Armine Hovakimyan ◽

Karen Zagorski ◽

Tatevik Antonyan ◽

Irina Petrushina ◽

...

Keyword(s):

Dna Vaccines ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Lewy Bodies ◽

Amyloid Β ◽

The Elderly ◽

Brain Regions ◽

Dependent Manner ◽

Lewy Neurites ◽

The Brain

AbstractAccumulation of misfolded proteins such as amyloid-β (Aβ), tau, and α-synuclein (α-Syn) in the brain leads to synaptic dysfunction, neuronal damage, and the onset of relevant neurodegenerative disorder/s. Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are characterized by the aberrant accumulation of α-Syn intracytoplasmic Lewy body inclusions and dystrophic Lewy neurites resulting in neurodegeneration associated with inflammation. Cell to cell propagation of α-Syn aggregates is implicated in the progression of PD/DLB, and high concentrations of anti-α-Syn antibodies could inhibit/reduce the spreading of this pathological molecule in the brain. To ensure sufficient therapeutic concentrations of anti-α-Syn antibodies in the periphery and CNS, we developed four α-Syn DNA vaccines based on the universal MultiTEP platform technology designed especially for the elderly with immunosenescence. Here, we are reporting on the efficacy and immunogenicity of these vaccines targeting three B-cell epitopes of hα-Syn aa85–99 (PV-1947D), aa109–126 (PV-1948D), aa126–140 (PV-1949D) separately or simultaneously (PV-1950D) in a mouse model of synucleinopathies mimicking PD/DLB. All vaccines induced high titers of antibodies specific to hα-Syn that significantly reduced PD/DLB-like pathology in hα-Syn D line mice. The most significant reduction of the total and protein kinase resistant hα-Syn, as well as neurodegeneration, were observed in various brain regions of mice vaccinated with PV-1949D and PV-1950D in a sex-dependent manner. Based on these preclinical data, we selected the PV-1950D vaccine for future IND enabling preclinical studies and clinical development.

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Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Biomolecules ◽

10.3390/biom10030391 ◽

2020 ◽

Vol 10 (3) ◽

pp. 391 ◽

Cited By ~ 6

Author(s):

Margaux Teil ◽

Marie-Laure Arotcarena ◽

Emilie Faggiani ◽

Florent Laferriere ◽

Erwan Bezard ◽

...

Keyword(s):

Parkinson’S Disease ◽

Clinical Trials ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Curative Treatment ◽

Preclinical Studies ◽

Cytoplasmic Inclusions ◽

The Many ◽

The Brain

Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Models for LRRK2-Linked Parkinsonism

Parkinson s Disease ◽

10.4061/2011/942412 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 9

Author(s):

Tianxia Li ◽

DeJun Yang ◽

Sarah Sushchky ◽

Zhaohui Liu ◽

Wanli W. Smith

Keyword(s):

Dopaminergic Neurons ◽

Autosomal Dominant ◽

Dopaminergic System ◽

Late Onset ◽

Lewy Bodies ◽

Leucine Rich Repeat ◽

Protein Deposition ◽

Lrrk2 Gene ◽

The Brain ◽

Potential Therapeutics

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD is not fully understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death progression in the dopaminergic system and abnormal protein deposition in the brain is not yet available. Recently, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified to cause autosomal-dominant late-onset PD and contribute to sporadic PD. Here, we review the recent models for LRRK2-linked Parkinsonism and their utility in studying LRRK2 neurobiology, pathogenesis, and potential therapeutics.

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Nrf2 inducer and cncC overexpression attenuates neurodegeneration due to α-synuclein in Drosophila

Biochemistry and Cell Biology ◽

10.1139/bcb-2015-0015 ◽

2015 ◽

Vol 93 (4) ◽

pp. 351-358 ◽

Cited By ~ 18

Author(s):

Bing Wang ◽

Qingqing Liu ◽

Hongyun Shan ◽

Chunlin Xia ◽

Zhaohui Liu

Keyword(s):

Signaling Pathway ◽

Dopaminergic Neurons ◽

Autosomal Dominant ◽

Lewy Bodies ◽

Antioxidant Response ◽

Homologous Gene ◽

Major Protein ◽

Selective Expression ◽

The Brain ◽

Transgenic Flies

The study of the genes that are related to the pathogenesis of Parkinson’s disease (PD) will improve our understanding of the mechanisms that underlie the development of PD. α-Synuclein is a major protein component of Lewy bodies, which are characteristic structures of PD pathology. Mutations in α-synuclein are closely related to the early onset of autosomal dominant PD. Transgenic flies with mutant α-synuclein (A53T) display neurodegenerative changes that include movement dysfunctions and a loss of dopaminergic neurons in the brain. In the present study, we measured reactive oxygen species (ROS) levels in α-synuclein transgenic flies by monitoring the fluorescence levels of redox-sensitive indicators based on GFP (roGFP) in flies co-expressing roGFP and mutant α-synuclein. We found that the ROS levels were significantly increased in the mutant α-synuclein flies. The elevations in ROS levels were also proportionate to the behavioral disorders and the losses of dopaminergic neurons. We also found that CDDO-Me inhibited the increases in ROS levels in the A53T flies and improved the neurodegenerative changes by activating the Nrf2/antioxidant response element signaling pathway. Selective expression of the Nrf2 homologous gene cncC in the dopaminergic neurons effectively protected against the neurodegenerative phenotype of the A53T α-synuclein flies, compared to the flies that expressed cncC in all neurons. These results indicate that the reductions in oxidative stress that are mediated by the activation of the antioxidant signaling pathway can effectively attenuate the neurotoxicity caused by mutations in α-synuclein.

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Brief practical clinical diagnostic criteria for the neurodegenerative diseases in the elderly

Drugs and Therapy Studies ◽

10.4081/dts.2011.e6 ◽

2011 ◽

Vol 1 (1) ◽

pp. 6 ◽

Cited By ~ 1

Author(s):

Fulvio Lauretani ◽

Paolo Caffarra ◽

Livia Ruffini ◽

Anna Nardelli ◽

Gian Paolo Ceda ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Cognitive Deficits ◽

Lewy Bodies ◽

The Elderly ◽

Motor Symptoms ◽

Imaging Features ◽

One Year ◽

The Moment ◽

Clinical Diagnostic Criteria

In the literature there is need of clinical and instrumental characterization of all neurodegenerative diseases. Particular attention deserves the timing of the onset of motor or cognitive symptoms, which is extremely useful issue giving the frequent overlapping between neurodegenerative diseases. Aim of this review is to provide a description of typical clinical and imaging features of all neurodegenerative diseases, especially idiopathic Parkinson’s disease (PD) and Alzheimer’s disease (AD). Particular attention will be devoted to the cluster of symptoms at the moment of the diagnosis. Based on early starting symptoms (cognitive or extrapiramidal) we will introduce criteria to differentiate AD from fronto-Temporal Dementia (FTD), Lewy bodies dementia (DLB) and Vascular dementia (VaD), and between PD, Vascular Parkinsonism (VP) and DLB. All these diseases are characterized by cognitive deficits. PD will be suspected if cognitive impairment occurs at least one year after the onset of the motor symptoms while VP and DLB are more likely if cognitive deficits and motor symptoms appear simultaneously. Finally, we will focus on parkinsonian signs plus other motor symptoms at the time of the diagnosis. The presence of cerebellar or pyramidal signs, with falls and autonomic dysfunction, with or without cognitive deficit should help to consider potential causes of atypical parkinsonism including cortical-basal degeneration (CBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).

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Aggresome formation and segregation of inclusions influence toxicity of α-synuclein and synphilin-1 in yeast

Biochemical Society Transactions ◽

10.1042/bst0391476 ◽

2011 ◽

Vol 39 (5) ◽

pp. 1476-1481 ◽

Cited By ~ 16

Author(s):

Erwin Swinnen ◽

Sabrina Büttner ◽

Tiago F. Outeiro ◽

Marie-Christine Galas ◽

Frank Madeo ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Elderly Population ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

The Elderly ◽

Interacting Protein ◽

Protein Deposits ◽

Ring Complex ◽

Aggresome Formation

PD (Parkinson's disease) is a neurodegenerative disorder, caused by a selective loss of dopaminergic neurons in the substantia nigra, which affects an increasing number of the elderly population worldwide. One of the major hallmarks of PD is the occurrence of intracellular protein deposits in the dying neurons, termed Lewy bodies, which contain different proteins, including aggregated α-synuclein and its interacting protein synphilin-1. During the last decade, a number of groups developed yeast models that reproduced important features of PD and allowed the deciphering of pathways underlying the cytotoxicity triggered by α-synuclein. Here, we review the recent contributions obtained with yeast models designed to study the presumed pathobiology of synphilin-1. These models pointed towards a crucial role of the sirtuin Sir2 and the chaperonin complex TRiC (TCP-1 ring complex)/CCT (chaperonin containing TCP-1) in handling misfolded and aggregated proteins.

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Effect of Myricetin on the Loss of Dopaminergic Neurons in the Transgenic Drosophila Model of Parkinson’s Disease

Current Drug Therapy ◽

10.2174/1574885513666180529114546 ◽

2019 ◽

Vol 14 (1) ◽

pp. 58-64 ◽

Cited By ~ 3

Author(s):

Gulshan Ara ◽

Mohammad Afzal ◽

Smita Jyoti ◽

Falaq Naz ◽

Rahul ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Neuronal Damage ◽

Radical Scavenging ◽

Lewy Bodies ◽

Dopamine Content ◽

Drosophila Model ◽

Dose Dependent ◽

The Brain

Background: The formation of Lewy bodies is associated with the production of reactive oxygen species (ROS) and the neuronal damage specifically the dopaminergic neurons in the Parkinson’s disease patients. Hence any agent that could curtail the production of ROS /oxidative stress could act as a possible therapeutic agent thereby preventing the neuronal damage. Method: In the present study, we first evaluated the antioxidant potential of myricetin by performing superoxide anion scavenging and diphenyl-picrylhydrazyl (DPPH) free radical scavenging assays. Myricetin at a final concentration of 10, 20 and 40µM was mixed in diet and the PD flies were allowed to feed on it for 24 days. After 24 days of exposure, the dopamine content was estimated in brain and the immunohistochemistry was performed for the tyroxine hydroxylase activity on the brain sections from each group. Results: Myricetin showed a dose-dependent increase in the antioxidative activity. The exposure of PD flies to 10, 20 and 40µM of Myricetin not only showed a dose-dependent significant increase in the dopamine content compared to unexposed PD flies (p<0.05), but also prevented the loss of dopaminergic neurons in the brain of PD flies. Conclusion: The results suggest that the antioxidative potential of myricetin is responsible for preventing the loss of dopaminergic neurons and dopamine content.

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The Gut–Brain Axis and Its Relation to Parkinson’s Disease: A Review

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.782082 ◽

2022 ◽

Vol 13 ◽

Author(s):

Emily M. Klann ◽

Upuli Dissanayake ◽

Anjela Gurrala ◽

Matthew Farrer ◽

Aparna Wagle Shukla ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Current Knowledge ◽

Lewy Bodies ◽

Disease Diagnosis ◽

Alpha Synuclein ◽

Motor Symptoms ◽

Abnormal Gait ◽

Non Motor Symptoms ◽

The Brain

Parkinson’s disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the substantia nigra and other related circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome–gut–brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome–gut–brain axis might play in the underlying pathological mechanisms of Parkinson’s disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson’s disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome–gut–brain axis in the context of Parkinson’s disease.

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-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies

International Journal of Alzheimer s Disease ◽

10.1155/2012/437025 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Kensaku Kasuga ◽

Masatoyo Nishizawa ◽

Takeshi Ikeuchi

Keyword(s):

Dementia With Lewy Bodies ◽

Biological Fluids ◽

Lewy Bodies ◽

The Elderly ◽

Sample Collection ◽

Intracellular Protein ◽

Blood Contamination ◽

Lewy Neurites ◽

Potential Biomarker ◽

The Brain

Dementia with Lewy bodies (DLB) is a common subtype of dementia in the elderly. DLB is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites, both of which are composed ofα-synuclein. Althoughα-synuclein was initially considered to be an exclusively intracellular protein, it has been found to be secreted into biological fluids.α-Synuclein in biological fluids such as cerebrospinal fluid (CSF) and blood has been discussed as a potential biomarker of DLB andα-synuclein-related disorders, becauseα-synuclein is characteristically accumulated in the brain of patients with these disorders. Theα-synuclein level in CSF has been examined by several investigators, and the majority of studies have shown a reduction in CSFα-synuclein level in DLB andα-synuclein-related disorders. Discrepant findings of studies of plasmaα-synuclein level in patients with DLB have been reported. Because the level ofα-synuclein stored in red blood cells is considerably high, blood contamination and haemolysis during sample collection and processing should be considered as a confounding factor for quantification ofα-synuclein. Here, the recent progress in the studies ofα-synuclein as a biomarker of DLB and their potential clinical applications are reviewed.

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