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Parkinson Disease: HELP
Articles from South Africa
Based on 69 articles published since 2008
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These are the 69 published articles about Parkinson Disease that originated from South Africa during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline Guideline for the treatment of Parkinson's disease. 2009

Carr, J / Kies, B / Fine, J / Anonymous220650. ·jcarr@sun.ac.za ·S Afr Med J · Pubmed #20128276.

ABSTRACT: -- No abstract --

2 Editorial A putative founder effect for Parkinson's disease in South African Afrikaners. 2014

Carr, Jonathan / van Coller, Riaan. ·Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa. jcarr@sun.ac.za. ·S Afr Med J · Pubmed #25214249.

ABSTRACT: -- No abstract --

3 Review Early Life Stress, Depression And Parkinson's Disease: A New Approach. 2018

Dallé, Ernest / Mabandla, Musa V. ·School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa. dumessherve@yahoo.fr. · School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa. ·Mol Brain · Pubmed #29551090.

ABSTRACT: This review aims to shed light on the relationship that involves exposure to early life stress, depression and Parkinson's disease (PD). A systematic literature search was conducted in Pubmed, MEDLINE, EBSCOHost and Google Scholar and relevant data were submitted to a meta-analysis . Early life stress may contribute to the development of depression and patients with depression are at risk of developing PD later in life. Depression is a common non-motor symptom preceding motor symptoms in PD. Stimulation of regions contiguous to the substantia nigra as well as dopamine (DA) agonists have been shown to be able to attenuate depression. Therefore, since PD causes depletion of dopaminergic neurons in the substantia nigra, depression, rather than being just a simple mood disorder, may be part of the pathophysiological process that leads to PD. It is plausible that the mesocortical and mesolimbic dopaminergic pathways that mediate mood, emotion, and/or cognitive function may also play a key role in depression associated with PD. Here, we propose that a medication designed to address a deficiency in serotonin is more likely to influence motor symptoms of PD associated with depression. This review highlights the effects of an antidepressant, Fluvoxamine maleate, in an animal model that combines depressive-like symptoms and Parkinsonism.

4 Review Therapeutic, Molecular and Computational Aspects of Novel Monoamine Oxidase (MAO) Inhibitors. 2017

Ramesh, Muthusamy / Dokurugu, Yussif M / Thompson, Michael D / Soliman, Mahmoud E. ·Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban- 4001. South Africa. · Molecular Modeling and Drug Design Research Group, College of Pharmacy and Pharmaceutical Science Research Center, Florida Agricultural and Mechanical University (FAMU), Tallahassee, Florida 32307. United States. ·Comb Chem High Throughput Screen · Pubmed #28294055.

ABSTRACT: Background Due to the limited number of MAO inhibitors in the clinics, several research efforts are aimed at the discovery of novel MAO inhibitors. At present, a high specificity and a reversible mode of inhibition of MAO-A/B are cited as desirable traits in drug discovery process. This will help to reduce the probability of causing target disruption and may increase the duration of action of drug. AIM: Most of the existing MAO inhibitors lead to side effects due to the lack of affinity and selectivity. Therefore, there is an urgent need to design novel, potent, reversible and selective inhibitors for MAO-A/B. Selective inhibition of MAO-A results in the elevated level of serotonin and noradrenaline. Hence, MAO-A inhibitors can be used for improving the symptoms of depression. The selective MAO-B inhibitors are used with L-DOPA and/or dopamine agonists in the symptomatic treatment of Parkinson's disease. The present study was aimed to describe the recently developed hits of MAO inhibitors. METHOD: At present, CADD techniques are gaining an attention in rationale drug discovery of MAO inhibitors, and several research groups employed CADD approaches on various chemical scaffolds to identify novel MAO inhibitors. These computational techniques assisted in the development of lead molecules with improved pharmacodynamics / pharmacokinetic properties toward MAOs. Further, CADD techniques provided a better understanding of structural aspects of molecular targets and lead molecules. CONCLUSIONS: The present review describes the importance of structural features of potential chemical scaffolds as well as the role of computational approaches like ligand docking, molecular dynamics, QSAR and pharmacophore modeling in the development of novel MAO inhibitors.

5 Review Improving drug delivery technology for treating neurodegenerative diseases. 2016

Choonara, Yahya E / Kumar, Pradeep / Modi, Girish / Pillay, Viness. ·a Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Science, Faculty of Health Sciences , University of the Witwatersrand, Johannesburg , South Africa. · b Division of Neurosciences, Department of Neurology, Faculty of Health Sciences , University of the Witwatersrand, Johannesburg , South Africa. ·Expert Opin Drug Deliv · Pubmed #26967508.

ABSTRACT: INTRODUCTION: Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified. AREAS COVERED: This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms. EXPERT OPINION: Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer's disease and Parkinson's disease. However, much work is still required in this field beyond the preclinical testing phase.

6 Review Advances in GBA-associated Parkinson's disease--Pathology, presentation and therapies. 2016

Barkhuizen, Melinda / Anderson, David G / Grobler, Anne F. ·DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, 2520, South Africa; Department of Paediatrics, School for Mental Health and Neuroscience, Maastricht University, Maastricht, 6229, The Netherlands. Electronic address: melinda.barkhuizen@gmail.com. · Department of Neurology, Witwatersrand University Donald Gordon Medical Centre, Parktown, Johannesburg, 2193, South Africa. · DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, 2520, South Africa. ·Neurochem Int · Pubmed #26743617.

ABSTRACT: GBA mutations are to date the most common genetic risk factor for Parkinson's disease. The GBA gene encodes the lysomal hydrolase glucocerebrosidase. Whilst bi-allelic GBA mutations cause Gaucher disease, both mono- and bi-allelic mutations confer risk for Parkinson's disease. Clinically, Parkinson's disease patients with GBA mutations resemble idiopathic Parkinson's disease patients. However, these patients have a modest reduction in age-of-onset of disease and a greater incidence of cognitive decline. In some cases, GBA mutations are also responsible for familial Parkinson's disease. The accumulation of α-synuclein into Lewy bodies is the central neuropathological hallmark of Parkinson's disease. Pathologic GBA mutations reduce enzymatic function. A reduction in glucocerebrosidase function increases α-synuclein levels and propagation, which in turn inhibits glucocerebrosidase in a feed-forward cascade. This cascade is central to the neuropathology of GBA-associated Parkinson's disease. The lysosomal integral membrane protein type-2 is necessary for normal glucocerebrosidase function. Glucocerebrosidase dysfunction also increases in the accumulation of β-amyloid and amyloid-precursor protein, oxidative stress, neuronal susceptibility to metal ions, microglial and immune activation. These factors contribute to neuronal death. The Mendelian Parkinson's disease genes, Parkin and ATP13A2, intersect with glucocerebrosidase. These factors sketch a complex circuit of GBA-associated neuropathology. To clinically interfere with this circuit, central glucocerebrosidase function must be improved. Strategies based on reducing breakdown of mutant glucocerebrosidase and increasing the fraction that reaches the lysosome has shown promise. Breakdown can be reduced by interfering with the ability of heat-shock proteins to recognize mutant glucocerebrosidase. This underlies the therapeutic efficacy of certain pharmacological chaperones and histone deacetylase inhibitors. These therapies are promising for Parkinson's disease, regardless of mutation status. Recently, there has been a boom in studies investigating the role of glucocerebrosidase in the pathology of Parkinson's disease. This merits a comprehensive review of the current cell biological processes and pathological pictures involving Parkinson's disease associated with GBA mutations.

7 Review Time to change the blind men and the elephant approach to Parkinson disease? 2015

Racette, Brad A / Willis, Allison W. ·From the Department of Neurology (B.A.R.), Washington University School of Medicine, St. Louis, MO · the School of Public Health (B.A.R.), Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa · and the Department of Neurology (A.W.W.) and the Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics (A.W.W.), University of Pennsylvania School of Medicine, Philadelphia. ·Neurology · Pubmed #26070339.

ABSTRACT: Parkinson disease (PD) is a progressive neurodegenerative disease that is associated with substantial morbidity and early mortality. Disease-related costs exceed $10 billion, not including medications, out-of-pocket expenses, or societal costs. Symptomatic treatment with levodopa, which has been available for over 30 years, and advanced therapies such as deep brain stimulation improve outcomes. Yet most new medications for PD provide a therapeutic benefit that is relatively modest compared to the benefits from levodopa. Despite dozens of neuroprotective clinical trials, there are no medications proven to slow the progression of the disease. Given these limitations, we provide evidence of the potential public health impact of a research agenda that emphasizes identification of risk factors to reduce disease burden through exposure mitigation. In addition, we emphasize health care policy that focuses on increasing health care expenditures for neurologic evaluation and management services to increase access to specialists to improve disease outcomes and reduce costs through better disease management.

8 Review Evidence for a common biological pathway linking three Parkinson's disease-causing genes: parkin, PINK1 and DJ-1. 2015

van der Merwe, Celia / Jalali Sefid Dashti, Zahra / Christoffels, Alan / Loos, Ben / Bardien, Soraya. ·Division of Molecular Biology & Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Cape Town, 7505, South Africa. ·Eur J Neurosci · Pubmed #25761903.

ABSTRACT: Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain. Autosomal recessive, early-onset cases of PD are predominantly caused by mutations in the parkin, PINK1 and DJ-1 genes. Animal and cellular models have verified a direct link between parkin and PINK1, whereby PINK1 phosphorylates and activates parkin at the outer mitochondrial membrane, resulting in removal of dysfunctional mitochondria via mitophagy. Despite the overwhelming evidence for this interaction, few studies have been able to identify a link for DJ-1 with parkin or PINK1. The aim of this review is to summarise the functions of these three proteins, and to analyse the existing evidence for direct and indirect interactions between them. DJ-1 is able to rescue the phenotype of PINK1-knockout Drosophila models, but not of parkin-knockouts, suggesting that DJ-1 may act in a parallel pathway to that of the PINK1/parkin pathway. To further elucidate a commonality between these three proteins, bioinformatics analysis established that Miro (RHOT1) interacts with parkin and PINK1, and HSPA4 interacts with all three proteins. Furthermore, 30 transcription factors were found to be common amongst all three proteins, with many of them being involved in transcriptional regulation. Interestingly, expression of these proteins and their associated transcription factors are found to be significantly down-regulated in PD patients compared to healthy controls. In summary, this review provides insight into common pathways linking three PD-causing genes and highlights some key questions, the answers to which may provide critical insight into the disease process.

9 Review Caffeine as a lead compound for the design of therapeutic agents for the treatment of Parkinson's disease. 2015

Petzer, Jacobus P / Petzer, Anel. ·Department of Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa. jacques.petzer@nwu.ac.za. ·Curr Med Chem · Pubmed #25544641.

ABSTRACT: The current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson's disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson's disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson's disease.

10 Review Manganism in the 21st century: the Hanninen lecture. 2014

Racette, Brad A. ·Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111, St. Louis, MO 63110, USA; University of the Witwatersrand, School of Public Health, Faculty of Health Sciences, Johannesburg, South Africa. Electronic address: racetteb@neuro.wustl.edu. ·Neurotoxicology · Pubmed #24148923.

ABSTRACT: Since the original description of the health effects of inhaled occupational manganese (Mn) by Couper in 1837, an extensive literature details the clinical syndrome and pathophysiology of what was thought to be a rare condition. In the last decade, conventional wisdom regarding the clinicopathological effects of Mn has been challenged. Past exposures to Mn were an order of magnitude higher than modern exposures in developed countries; therefore, the clinical syndrome seen in the time of Couper is no longer typical of modern Mn exposed workers. Parkinsonism (rigidity, bradykinesia, rest tremor, and postural instability) is present in 15% of Mn-exposed workers in welding industries, and these parkinsonian signs are associated with reduced health status and quality of life. These parkinsonian signs also overlap considerably with the clinical findings seen in early stages of Parkinson's disease (PD); although, molecular imaging suggests that Mn-exposed workers have dopaminergic dysfunction in a pattern unique from PD. Furthermore, geographic information system studies demonstrate that regions of the US with high industrial Mn emissions have an increased incidence of PD and increased PD associated mortality. This review will contrast historical, descriptive human studies in Mn-exposed subjects with more recent data and will suggest a research agenda for the 21st century.

11 Review The prevalence and genetics of Parkinson's disease in sub-Saharan Africans. 2013

Blanckenberg, Janine / Bardien, Soraya / Glanzmann, Brigitte / Okubadejo, Njideka U / Carr, Jonathan A. ·Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa. ·J Neurol Sci · Pubmed #24079843.

ABSTRACT: Parkinson's disease (PD) is under-studied in Black Sub-Saharan African (SSA) populations. To date, there have been only six prevalence and no incidence studies. The crude prevalence of PD in SSA varies from 7 to 20 per 100,000, which is appreciably lower than in Caucasian populations. There are a limited number of published studies (nine) on the genetic factors associated with PD in SSA populations. Mutations have been reported in the parkin gene, and are restricted to only three patients (two Black South Africans and one Zambian). No mutations have been identified in the LRRK2, SNCA, PINK, or DJ-1 genes. Given the unique ancestry of SSA populations, their inclusion in genetic studies may provide a substantial contribution to the identification of novel genetic factors and genetic-environmental interactions underlying this disorder. More initiatives are needed to drive further research on PD in these populations and to facilitate collaborative projects across Africa.

12 Review Attention and visual dysfunction in Parkinson's disease. 2012

Botha, Hugo / Carr, Jonathan. ·Division of Neurology, Department of Medicine, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, Cape Town, South Africa. ·Parkinsonism Relat Disord · Pubmed #22503538.

ABSTRACT: Visual processing extends from the retinal level to the ventral temporal lobe, and is modified by top-down and bottom-up processing. Complex visual hallucinations (VH) are commonly a feature of disorders which affect temporal lobe structures, frequently in association with impairment of ascending monoaminergic pathways. When Parkinson's disease (PD) is associated with VH, pathological changes characteristically affect the temporal lobes, a finding which is recapitulated by imaging findings. However, a major association of VH is with cognitive decline, and this is typically linked to deficits in attention and working memory, both of which are modulated by dopamine. Similarly, dopamine plays a crucial role in the function of prefrontal cortex, in addition to controlling access to consciousness via gating mechanisms that are dependent on the basal ganglia.

13 Review Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson's disease. 2011

Bardien, Soraya / Lesage, Suzanne / Brice, Alexis / Carr, Jonathan. ·Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa. ·Parkinsonism Relat Disord · Pubmed #21641266.

ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive and selective degeneration of nigrostriatal dopaminergic neurons. The discovery of at least six PD-causing genes in predominantly early-onset forms of the disorder has cemented a genetic component to the etiology. Notably, the discovery of mutations in the LRRK2 gene in patients presenting with typical 'sporadic' PD with ages at onset in their sixties and seventies has shifted paradigms in the field of PD research. The G2019S mutation in LRRK2 has been found in diverse populations worldwide and usually resides on a common haplotype revealing that many of these individuals share a common ancestor, probably of Middle Eastern origin. The only validated coding susceptibility alleles for PD, G2385R and R1628P, are both in this gene but to date have been found exclusively in Asian populations. Concomitant with genetic testing for PD is the need for appropriate and informed genetic counseling. Families of patients with LRRK2 mutations and susceptibility alleles need to be informed about the current lack of disease preventative strategies and the implications surrounding incomplete penetrance. In summary, single-handedly LRRK2 has had a major impact on the field of PD research and the findings have been of interest to both clinicians and scientists. We anticipate that other genes of such major impact exist for PD and look forward to their discovery.

14 Review Advances in the treatment of neurodegenerative disorders employing nanotechnology. 2010

Modi, Girish / Pillay, Viness / Choonara, Yahya E. ·Department of Neurology, Division of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa. gmodicns@mweb.co.za ·Ann N Y Acad Sci · Pubmed #20146696.

ABSTRACT: Due to limitations posed by the restrictive blood-brain barrier, conventional drug delivery systems do not provide adequate cyto-architecture restoration and connection patterns that are essential for functional recovery in neurodegenerative disorders (NDs). Nanotechnology employs engineered materials or devices that interact with biological systems at a molecular level and could revolutionize the treatment of NDs by stimulating, responding to, and interacting with target sites to induce physiological responses while minimizing side effects. This review provides a concise discussion of the current applications of nano-enabled drug-delivery systems for the treatment of NDs, in particular Alzheimer's and Parkinson's diseases, and explores the future applications of nanotechnology in clinical neuroscience to develop innovative therapeutic modalities for the treatment of NDs.

15 Review Levodopa delivery systems: advancements in delivery of the gold standard. 2010

Ngwuluka, Ndidi / Pillay, Viness / Du Toit, Lisa C / Ndesendo, Valence / Choonara, Yahya / Modi, Girish / Naidoo, Dinesh. ·University of the Witwatersrand, Department of Pharmacy and Pharmacology, 7 York Road, Parktown, 2193, Johannesburg, South Africa. ·Expert Opin Drug Deliv · Pubmed #20095943.

ABSTRACT: IMPORTANCE OF THE FIELD: Despite the fact that Parkinson's disease (PD) was discovered almost 200 years ago, its treatment and management remain immense challenges because progressive loss of dopaminergic nigral neurons, motor complications experienced by the patients as the disease progresses and drawbacks of pharmacotherapeutic management still persist. Various therapeutic agents have been used in the management of PD, including levodopa (l-DOPA), selegiline, amantadine, bromocriptine, entacapone, pramipexole dihydrochloride and more recently istradefylline and rasagiline. Of all agents, l-DOPA although the oldest, remains the most effective. l-DOPA is easier to administer, better tolerated, less expensive and is required by almost all PD patients. However, l-DOPA's efficacy in advanced PD is significantly reduced due to metabolism, subsequent low bioavailability and irregular fluctuations in its plasma levels. Significant strides have been made to improve the delivery of l-DOPA in order to enhance its bioavailability and reduce plasma fluctuations as well as motor complications experienced by patients purportedly resulting from pulsatile stimulation of the striatal dopamine receptors. AREAS COVERED IN THIS REVIEW: Drug delivery systems that have been instituted for the delivery of l-DOPA include immediate release formulations, liquid formulations, dispersible tablets, controlled release formulations, dual-release formulations, microspheres, infusion and transdermal delivery, among others. In this review, the l-DOPA-loaded drug delivery systems developed over the past three decades are elaborated. WHAT THE READER WILL GAIN: The ultimate aim was to assess critically the attempts made thus far directed at improving l-DOPA absorption, bioavailability and maintenance of constant plasma concentrations, including the drug delivery technologies implicated. TAKE HOME MESSAGE: This review highlights the fact that neuropharmaceutics is at a precipice, which is expected to spur investigators to take that leap to enable the generation of innovative delivery systems for the effective management of PD.

16 Review Trends in the molecular pathogenesis and clinical therapeutics of common neurodegenerative disorders. 2009

Choonara, Yahya E / Pillay, Viness / du Toit, Lisa C / Modi, Girish / Naidoo, Dinesh / Ndesendo, Valence M / Sibambo, Sibongile R. ·University of the Witwatersrand, Department of Pharmacy and Pharmacology, Parktown, Johannesburg, South Africa. ·Int J Mol Sci · Pubmed #19582217.

ABSTRACT: The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis and Huntington's disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders' in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions.

17 Review Nanotechnological applications for the treatment of neurodegenerative disorders. 2009

Modi, Girish / Pillay, Viness / Choonara, Yahya E / Ndesendo, Valence M K / du Toit, Lisa C / Naidoo, Dinesh. ·University of the Witwatersrand, School of Neurosciences, Department of Neurology, Parktown, 2193, Johannesburg, South Africa. ·Prog Neurobiol · Pubmed #19486920.

ABSTRACT: Nanotechnology employs engineered materials or devices that interact with biological systems at a molecular level and could revolutionize the treatment of neurodegenerative disorders (NDs) by stimulating, responding to and interacting with target sites to induce physiological responses while minimizing side-effects. Conventional drug delivery systems do not provide adequate cyto-architecture restoration and connection patterns that are essential for functional recovery in NDs, due to limitations posed by the restrictive blood-brain barrier. This review article provides a concise incursion into the current and future applications of nano-enabled drug delivery systems for the treatment of NDs, in particular Alzheimer's and Parkinson's diseases, and explores the application of nanotechnology in clinical neuroscience to develop innovative therapeutic modalities for the treatment of NDs.

18 Review Dual-target-directed drugs that block monoamine oxidase B and adenosine A(2A) receptors for Parkinson's disease. 2009

Petzer, Jacobus P / Castagnoli, Neal / Schwarzschild, Michael A / Chen, Jiang-Fan / Van der Schyf, Cornelis J. ·Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, 2520, South Africa. jacques.petzer@nwu.ac.za ·Neurotherapeutics · Pubmed #19110205.

ABSTRACT: Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A(2A) receptor is one such target. Antagonists of this receptor (A(2A) antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A(2A) antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A(2A) antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A(2A) receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

19 Review Neuroproteomics as a promising tool in Parkinson's disease research. 2008

Pienaar, Ilse S / Daniels, William M U / Götz, Jürgen. ·Department of Medical Physiology, University of Stellenbosch, Matieland, South Africa. ilse.pienaar@dpag.ox.ac.uk ·J Neural Transm (Vienna) · Pubmed #18523721.

ABSTRACT: Despite the vast number of studies on Parkinson's disease (PD), its effective diagnosis and treatment remains unsatisfactory. Hence, the relentless search for an optimal cure continues. The emergence of neuroproteomics, with its sophisticated techniques and non-biased ability to quantify proteins, provides a methodology with which to study the changes in neurons that are associated with neurodegeneration. Neuroproteomics is an emerging tool to establish disease-associated protein profiles, while also generating a greater understanding as to how these proteins interact and undergo post-translational modifications. Furthermore, due to the advances made in bioinformatics, insight is created concerning their functional characteristics. In this review, we first summarize the most prominent proteomics techniques and then discuss the major advances in the fast-growing field of neuroproteomics in PD. Ultimately, it is hoped that the application of this technology will lead towards a presymptomatic diagnosis of PD, and the identification of risk factors and new therapeutic targets at which pharmacological intervention can be aimed.

20 Clinical Trial Mitochondrial abnormality associates with type-specific neuronal loss and cell morphology changes in the pedunculopontine nucleus in Parkinson disease. 2013

Pienaar, Ilse S / Elson, Joanna L / Racca, Claudia / Nelson, Glyn / Turnbull, Douglass M / Morris, Christopher M. ·Centre for NeuroInflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, Hammersmith, United Kingdom. Electronic address: i.pienaar@imperial.ac.uk. · Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Centre for Human Metabolomics, Biochemistry Division, North-West University, Potchefstroom, South Africa. · Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom. · Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom. · Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; The Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom. · Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom; Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, United Kingdom. ·Am J Pathol · Pubmed #24099985.

ABSTRACT: Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN's normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow.

21 Article Lipopolysaccharide-binding protein (LBP) can reverse the amyloid state of fibrin seen or induced in Parkinson's disease. 2018

Pretorius, Etheresia / Page, Martin J / Mbotwe, Sthembile / Kell, Douglas B. ·Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa. · Department of Physiology, Faculty of Health Sciences, University of Pretoria, Arcadia, South Africa. · School of Chemistry, The University of Manchester, Manchester, Lancs, United Kingdom. · The Manchester Institute of Biotechnology, The University of Manchester, Manchester, Lancs, United Kingdom. ·PLoS One · Pubmed #29494603.

ABSTRACT: The thrombin-induced polymerisation of fibrinogen to form fibrin is well established as a late stage of blood clotting. It is known that Parkinson's Disease (PD) is accompanied by dysregulation in blood clotting, but it is less widely known as a coagulopathy. In recent work, we showed that the presence of tiny amounts of bacterial lipopolysaccharide (LPS) in healthy individuals could cause clots to adopt an amyloid form, and this could be observed via scanning electron microscopy (SEM) or via the fluorescence of thioflavin-T. This could be prevented by the prior addition of lipopolysaccharide-binding protein (LBP). We had also observed by SEM this unusual clotting in the blood of patients with Parkinson's Disease. We hypothesised, and here show, that this too can be prevented by LBP in the context of PD. This adds further evidence implicating inflammatory microbial cell wall products as an accompaniment to the disease, and may be part of its aetiology. This may lead to novel treatment strategies in PD designed to target microbes and their products.

22 Article Reward processing dysfunction in ventral striatum and orbitofrontal cortex in Parkinson's disease. 2018

du Plessis, Stéfan / Bossert, Meija / Vink, Matthijs / van den Heuvel, Leigh / Bardien, Soraya / Emsley, Robin / Buckle, Chanelle / Seedat, Soraya / Carr, Jonathan. ·Department of Psychiatry, Stellenbosch University, South Africa. Electronic address: stefandup@sun.ac.za. · University of Amsterdam, The Netherlands. Electronic address: meija.bossert@gmail.com. · Departments of Developmental and Experimental Psychology, Utrecht University, The Netherlands. Electronic address: m.vink2@uu.nl. · Department of Psychiatry, Stellenbosch University, South Africa. Electronic address: llvdh@sun.ac.za. · Division of Molecular Biology and Human Genetics, Stellenbosch University, South Africa. Electronic address: sbardien@sun.ac.za. · Department of Psychiatry, Stellenbosch University, South Africa. Electronic address: rae@sun.ac.za. · Department of Psychiatry, Stellenbosch University, South Africa. Electronic address: chanellebuckle@gmail.com. · Department of Psychiatry, Stellenbosch University, South Africa. Electronic address: sseedat@sun.ac.za. · Department of Neurology, Stellenbosch University, South Africa. Electronic address: jcarr@sun.ac.za. ·Parkinsonism Relat Disord · Pubmed #29307561.

ABSTRACT: BACKGROUND: Parkinson's disease is a growing concern as the longevity of the world's population steadily increases. Both ageing and Parkinson's disease have an impact on dopamine neurotransmission. It is therefore important to investigate their relative impact on the fronto-striatal reward system. There has been little investigation of reward processing in terms of anticipation and reward outcome in Parkinson's disease. Abnormal responses during reward processing have previously been demonstrated in whole-brain analysis of Parkinson's patients with mild lateralized disease, but the exact impact in regions specific to reward processing is still unknown. OBJECTIVE: Here we aim to investigate the impact of Parkinson's disease on the orbitofrontal ventral striatal reward system in patients with moderate to severe clinical symptoms. METHODS: We utilized a monetary incentive delay (MID) task in 17 Parkinson's patients who were compared to two control groups stratified by age. The MID paradigm reliably activates the ventral striatum during reward anticipation and the orbitofrontal cortex during reward outcome processing. RESULTS: Relative to the two control groups, Parkinson's disease patients had abnormal task related activity during both reward anticipation in the ventral striatum and reward outcome in the orbitofrontal cortex. There were no effects of ageing. CONCLUSION: These findings demonstrate abnormalities in anticipatory as well as reward outcome processing while treated primarily with levodopa. The orbitofrontal dysfunction during reward outcome processing may have specificity in Parkinson's disease, as it has been shown to be relatively unaffected by normal ageing.

23 Article Being on Target: Visual Information during Writing Affects Effective Connectivity in Parkinson's Disease. 2018

Nackaerts, Evelien / Michely, Jochen / Heremans, Elke / Swinnen, Stephan / Smits-Engelsman, Bouwien / Vandenberghe, Wim / Grefkes, Christian / Nieuwboer, Alice. ·Department of Rehabilitation Sciences, KU Leuven, Tervuursevest 101, Bus 1501, 3001 Heverlee, Belgium. Electronic address: evelien.nackaerts@kuleuven.be. · Department of Neurology, Cologne University Hospital, Kerpener Straße 62, 50924 Köln, Germany. Electronic address: jochen.michely@uk-koeln.de. · Department of Rehabilitation Sciences, KU Leuven, Tervuursevest 101, Bus 1501, 3001 Heverlee, Belgium. Electronic address: elke.heremans@kuleuven.be. · Department of Kinesiology, KU Leuven, Tervuursevest 101, Bus 1501, 3001 Heverlee, Belgium. Electronic address: stephan.swinnen@kuleuven.be. · Department of Health and Rehabilitation Sciences, University of Cape Town, Old Main Building Groote Schuur Hospital, Cape Town, South Africa. Electronic address: bouwienengelsman@icloud.com. · Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: wim.vandenberghe@uzleuven.be. · Department of Neurology, Cologne University Hospital, Kerpener Straße 62, 50924 Köln, Germany; Institute of Neuroscience and Medicine - Cognitive Neurology (INM-3), Research Centre Jülich, 52425 Jülich, Germany. Electronic address: christian.grefkes@uk-koeln.de. · Department of Rehabilitation Sciences, KU Leuven, Tervuursevest 101, Bus 1501, 3001 Heverlee, Belgium. Electronic address: alice.nieuwboer@kuleuven.be. ·Neuroscience · Pubmed #29294336.

ABSTRACT: A common motor symptom of Parkinson's disease (PD) is micrographia, characterized by a decrease in writing amplitude. Despite the relevance of this impairment for activities of daily living, the underlying neural network abnormalities and the impact of cueing strategies on brain connectivity are unknown. Therefore, we investigated the effects of visual cues on visuomotor network interactions during handwriting in PD and healthy controls (HCs). Twenty-eight patients with early disease, ON dopaminergic medication, and 14 age-matched controls performed a pre-writing task with and without visual cues in the scanner. Patients displayed weaker right visuo-parietal coupling than controls, suggesting impaired visuomotor integration during writing. Surprisingly, cueing did not have the expected positive effects on writing performance. Patients and controls, however, did activate similar networks during cued and uncued writing. During cued writing, the stronger influence of both visual and motor areas on the left superior parietal lobe suggested that visual cueing induced greater visual steering. In the absence of cues, there was enhanced coupling between parietal and supplementary motor areas (SMA) in line with previous findings in HCs during uncued motor tasks. In conclusion, the present study showed that patients with PD, despite their compromised brain function, were able to shift neural networks similar to controls. However, it seemed that visual cues provided a greater accuracy constraint on handwriting rather than offering unequivocal beneficial effects. Altogether, the results suggest that the effectiveness of using compensatory neural networks through applying external stimuli is task dependent and may compromise motor control during writing.

24 Article Temporal-Spatial Profiling of Pedunculopontine Galanin-Cholinergic Neurons in the Lactacystin Rat Model of Parkinson's Disease. 2018

Elson, Joanna L / Kochaj, Rafael / Reynolds, Richard / Pienaar, Ilse S. ·Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK. · Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa. · Wolfson Centre for Age-Related Diseases, King's College London, Guys Campus, London, SE1 1UL, UK. · Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, W12 ONN, London, UK. · Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, W12 ONN, London, UK. I.S.Pienaar@sussex.ac.uk. · School of Life Sciences, University of Sussex, Sussex House, Falmer, Brighton, BN1 9RH, UK. I.S.Pienaar@sussex.ac.uk. ·Neurotox Res · Pubmed #29218504.

ABSTRACT: Parkinson's disease (PD) is conventionally seen as resulting from single-system neurodegeneration affecting nigrostriatal dopaminergic neurons. However, accumulating evidence indicates multi-system degeneration and neurotransmitter deficiencies, including cholinergic neurons which degenerate in a brainstem nucleus, the pedunculopontine nucleus (PPN), resulting in motor and cognitive impairments. The neuropeptide galanin can inhibit cholinergic transmission, while being upregulated in degenerating brain regions associated with cognitive decline. Here we determined the temporal-spatial profile of progressive expression of endogenous galanin within degenerating cholinergic neurons, across the rostro-caudal axis of the PPN, by utilizing the lactacystin-induced rat model of PD. First, we show progressive neuronal death affecting nigral dopaminergic and PPN cholinergic neurons, reflecting that seen in PD patients, to facilitate use of this model for assessing the therapeutic potential of bioactive peptides. Next, stereological analyses of the lesioned brain hemisphere found that the number of PPN cholinergic neurons expressing galanin increased by 11%, compared to sham-lesioned controls, and increasing by a further 5% as the neurodegenerative process evolved. Galanin upregulation within cholinergic PPN neurons was most prevalent closest to the intra-nigral lesion site, suggesting that galanin upregulation in such neurons adapt intrinsically to neurodegeneration, to possibly neuroprotect. This is the first report on the extent and pattern of galanin expression in cholinergic neurons across distinct PPN subregions in both the intact rat CNS and lactacystin-lesioned rats. The findings pave the way for future work to target galanin signaling in the PPN, to determine the extent to which upregulated galanin expression could offer a viable treatment strategy for ameliorating PD symptoms associated with cholinergic degeneration.

25 Article Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents. 2018

Carradori, Simone / Ortuso, Francesco / Petzer, Anél / Bagetta, Donatella / De Monte, Celeste / Secci, Daniela / De Vita, Daniela / Guglielmi, Paolo / Zengin, Gokhan / Aktumsek, Abdurrahman / Alcaro, Stefano / Petzer, Jacobus P. ·Department of Pharmacy, "G. D'Annunzio" University of Chieti-Pescara, Via Dei Vestini 31, 66100 Chieti, Italy. · Dipartimento di Scienze Della Salute, University "Magna Graecia" of Catanzaro, Campus "S. Venuta", Viale Europa, 88100 Catanzaro, Italy. Electronic address: ortuso@unicz.it. · Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa. · Dipartimento di Chimica e Tecnologie Del Farmaco, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy. · Dipartimento di Chimica e Tecnologie Del Farmaco, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: daniela.secci@uniroma1.it. · Selcuk University, Science Faculty, Department of Biology, Konya, Turkey. · Dipartimento di Scienze Della Salute, University "Magna Graecia" of Catanzaro, Campus "S. Venuta", Viale Europa, 88100 Catanzaro, Italy. ·Eur J Med Chem · Pubmed #29126727.

ABSTRACT: New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual-target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19.

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