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ACS Chemical Neuroscience Aug 2023Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA,... (Review)
Review
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA, it has been the most prescribed drug for symptomatic relief in PD, whose prolonged use, however, causes undesirable motor fluctuations like dyskinesia and dystonia. Further, therapeutics targeting the pathological hallmarks of PD including α-synuclein aggregation, oxidative stress, neuroinflammation, and autophagy impairment have also been developed, yet PD treatment is a largely unmet success. The inception of the nanovesicle-based drug delivery approach over the past few decades brings add-on advantages to the therapeutic strategies for PD treatment in which nanovesicles (basically phospholipid-containing artificial structures) are used to load and deliver drugs to the target site of the body. The present review narrates the characteristic features of nanovesicles including their blood-brain barrier permeability and ability to reach dopaminergic neurons of the brain and finally discusses the current status of this technology in the treatment of PD. From the review, it becomes evident that with the assistance of nanovesicle technology, the therapeutic efficacy of anti-PD pharmaceuticals, phyto-compounds, as well as that of nucleic acids targeting α-synuclein aggregation gained a significant increment. Furthermore, owing to the multiple drug-carrying abilities of nanovesicles, combination therapy targeting multiple pathogenic events of PD has also found success in preclinical studies and will plausibly lead to effective treatment strategies in the near future.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Dopamine; Levodopa; Brain; Dopaminergic Neurons
PubMed: 37534999
DOI: 10.1021/acschemneuro.3c00070 -
Experimental Biology and Medicine... May 2023The economic and visual burdens associated with age-related macular degeneration (AMD) are expected to significantly increase in the coming years. As of now,... (Review)
Review
The economic and visual burdens associated with age-related macular degeneration (AMD) are expected to significantly increase in the coming years. As of now, interventions to delay or prevent AMD are limited. Hence, there is an urgent and unmet need to expand our therapeutic tools for AMD in a manner, that is, both efficient and cost-effective. In this review, we consider the idea of drug repurposing, in which existing medications with other indications can be re-imagined for treating AMD. We detail the results of several population-level studies that have shown associations between several candidates and decreased risk of AMD development or progression. Such candidates include the more extensively studied metformin and statins, in addition to recently identified candidates fluoxetine and DOPA (levodopa) that show promise. We then briefly explore results from an advanced bioinformatics study, which provides further evidence that existing medications are associated with AMD risk genes. Many of these candidates warrant further study in prospective, clinical trials, where their potential causal relationships with AMD can be thoroughly assessed.
Topics: Humans; Prospective Studies; Drug Repositioning; Macular Degeneration; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Levodopa; Data Mining
PubMed: 37452694
DOI: 10.1177/15353702231181188 -
Biosensors Oct 2022The interaction of tyrosinase with sulfonated starch--polyaniline@graphene (SSt--PANI@G) nanocomposite was investigated by electrochemical methods. The activity of the...
The interaction of tyrosinase with sulfonated starch--polyaniline@graphene (SSt--PANI@G) nanocomposite was investigated by electrochemical methods. The activity of the immobilized tyrosinase (Tyase) was proved by the electrochemical detection of three substrates (L-dopa, caffeic acid, and catechol). The SSt--PANI@G nanocomposite was characterized by Fourier-transform infrared spectra (FT-IR), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray analysis (EDX), and thermogravimetric analysis (TGA). To immobilize tyrosinase on the surface of the nanocomposite, a simple drop-casting technique was used. The presence of sulfuric acid and hydroxyl groups in SSt, amine groups in PANI, and high surface-to-volume ratio and electrical conductivity of graphene in the prepared nanocomposite led to good enzyme immobilization on the electrode surface. The modified electrode showed a suitable catalytic effect on the electrochemical redox agent, compared with the bare electrode. The peak current responses for three substrates were studied with a calibration curve derived using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). In addition, the fabricated SSt-g-PANI@G/Tyase/GCE showed a more suitable response to catechol, L-dopa, and caffeic acid substrates, respectively.
Topics: Graphite; Monophenol Monooxygenase; Spectroscopy, Fourier Transform Infrared; Starch; Levodopa; Nanocomposites; Electric Conductivity
PubMed: 36354447
DOI: 10.3390/bios12110939 -
NeuroImage Dec 2022Previous studies indicate a role of dopamine in spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not... (Randomized Controlled Trial)
Randomized Controlled Trial
Previous studies indicate a role of dopamine in spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not well understood whether dopamine directly affects these representations, or only impacts other aspects of spatial brain function. Moreover, both dopamine and spatial cognition decline sharply during age, raising the question which effect dopamine has on directional signals in the brain of older adults. To investigate these questions, we used a double-blind cross-over L-DOPA/Placebo intervention design in which 43 younger and 37 older adults navigated in a virtual spatial environment while undergoing functional magnetic resonance imaging (fMRI). We studied the effect of L-DOPA, a dopamine precursor, on fMRI activation patterns that encode spatial walking directions that have previously been shown to lose specificity with age. This was done in predefined regions of interest, including the early visual cortex, retrosplenial cortex, and hippocampus. Classification of brain activation patterns associated with different walking directions was improved across all regions following L-DOPA administration, suggesting that dopamine broadly enhances neural representations of direction. No evidence for differences between regions was found. In the hippocampus these results were found in both age groups, while in the retrosplenial cortex they were only observed in younger adults. Taken together, our study provides evidence for a link between dopamine and the specificity of neural responses during spatial navigation. SIGNIFICANCE STATEMENT: The sense of direction is an important aspect of spatial navigation, and neural representations of direction can be found throughout a large network of space-related brain regions. But what influences how well these representations track someone's true direction? Using a double-blind cross-over L-DOPA/Placebo intervention design, we find causal evidence that the neurotransmitter dopamine impacts the fidelity of direction selective neural representations in the human hippocampus and retrosplenial cortex. Interestingly, the effect of L-DOPA was either equally present or even smaller in older adults, despite the well-known age related decline of dopamine. These results provide novel insights into how dopamine shapes the neural representations that underlie spatial navigation.
Topics: Humans; Aged; Levodopa; Dopamine; Spatial Navigation; Brain Mapping; Magnetic Resonance Imaging
PubMed: 36243268
DOI: 10.1016/j.neuroimage.2022.119670 -
Expert Opinion on Therapeutic Patents Dec 2019: Parkinson's disease (PD), is a disorder debilitant characterized by the reduction of nigrostriatal dopaminergic neurons within the midbrain, specifically in the... (Review)
Review
: Parkinson's disease (PD), is a disorder debilitant characterized by the reduction of nigrostriatal dopaminergic neurons within the midbrain, specifically in the substantia nigra pars compacta, which results for the dopamine (DA) depletion in the striatum. Dopamine replacement therapies with the 3,4-dihydroxy-L-phenylalanine (Levodopa or L-DOPA) represent the most common strategy to treat PD. However, chronic administration of L-DOPA results in abnormal involuntary movement (AIMs). Thus, the present study aimed to prospect patents of alternative treatment strategies for L-DOPA-induced dyskinesias.: This review covers the therapeutic patents published over the 2001-2019 period in the WIPO, INPI, and ESPACENET, which report treatment strategies for L-DOPA induced dyskinesias (LIDs).: In recent years, several pharmaceutical companies, as well as universities and researchers have tested effective compounds for LIDs treatment, showing substances that act on central pathways as antagonists and agonists of the serotonergic system, which may result in the key to onset of LIDs in animal models of PD. Future works aiming to elucidate the L-DOPA, Flibanserin, Eltoprazine, and Pridopidina mechanisms of action on the receptors of the serotonergic system and D receptors of the indirect pathway, will allow the development of effective therapies for LIDs.
Topics: Animals; Antiparkinson Agents; Disease Models, Animal; Dopamine; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease; Patents as Topic
PubMed: 31694421
DOI: 10.1080/13543776.2019.1690453 -
The Analyst Jul 2023Melanin nanoparticles (NPs) have important biological functions including photoprotection and colouration, and artificial melanin-like NPs are relevant for catalysis,...
Melanin nanoparticles (NPs) have important biological functions including photoprotection and colouration, and artificial melanin-like NPs are relevant for catalysis, drug delivery, diagnosis and therapy. Despite their importance, the optical properties of single melanin NPs have not been measured. We combine quantitative differential interference contrast (qDIC) and extinction microscopy to characterise the optical properties of single NPs, both naturally sourced from cuttlefish ink, as well as synthetic NPs using polydopamine (PDA) and L-3,4-dihydroxyphenylalanine (L-DOPA). Combining qDIC with extinction, we determine the absorption index of individual NPs. We find that on average the natural melanin NPs have a higher absorption index than the artificial melanin NPs. From the analysis of the polarisation-dependent NP extinction, the NP aspect ratio is determined, with mean values at 405 nm wavelength in agreement with transmission electron microscopy. At longer wavelengths, we observe an additional optical anisotropy which is attributed to dichroism by structural ordering of the melanin. Our quantitative analysis yields a dichroism of 2-10% of the absorption index, increasing with wavelength from 455 nm to 660 nm for L-DOPA and PDA. Such an in-depth quantification of the optical properties of single melanin NPs is important for the design and future application of these ubiquitous bionanomaterials.
Topics: Melanins; Levodopa; Nanoparticles
PubMed: 37382583
DOI: 10.1039/d3an00654a -
Neurochemistry International Jun 2022Neurotransmitters are considered as a fundamental regulator in the process of neuronal growth, differentiation and survival. Parkinson's Disease (PD) occurs due to... (Review)
Review
Neurotransmitters are considered as a fundamental regulator in the process of neuronal growth, differentiation and survival. Parkinson's Disease (PD) occurs due to extensive damage of dopamine-producing neurons; this causes dopamine deficits in the midbrain, followed by the alternation of various other neurotransmitters (glutamate, GABA, serotonin, etc.). It has been observed that fluctuation of neurotransmission in the basal ganglia exhibits a great impact on the pathophysiology of PD. Dopamine replacement therapy, such as the use of L-DOPA, can increase the dopamine level, but it majorly ameliorates the motor symptoms and is also associated with long-term complications (for e.g., LID). While the non-dopaminergic system can efficiently target non-motor symptoms, for instance, the noradrenergic system regulates the synthesis of BDNF via the MAPK pathway, which is important in learning and memory. Herein, we briefly discuss the role of different neurotransmitters, implementation of neurotransmitter receptors in PD. We also illustrate the recent advances of neurotransmitter-based drugs, which are currently under in vivo and clinical studies. Reinstating normal neurotransmitter levels has been believed to be advantageous in the treatment of PD. Thus, there is an increasing demand for drugs that can specifically target the neurotransmission system and reinstate the normal levels of neurotransmitters, which might prevent or delay neurodegeneration in PD.
Topics: Basal Ganglia; Dopamine; Humans; Levodopa; Neurotransmitter Agents; Parkinson Disease
PubMed: 35331828
DOI: 10.1016/j.neuint.2022.105327 -
Expert Opinion on Pharmacotherapy May 2022
Topics: Antiparkinson Agents; Humans; Levodopa; Parkinson Disease
PubMed: 35212594
DOI: 10.1080/14656566.2022.2045275 -
Movement Disorders : Official Journal... Aug 2021Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal... (Review)
Review
Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Activities of Daily Living; Antiparkinson Agents; Carbidopa; Drug Combinations; Gels; Humans; Levodopa; Parkinson Disease; Quality of Life
PubMed: 33899262
DOI: 10.1002/mds.28595 -
Handbook of Clinical Neurology 2023One of the core pathological features of Parkinson's disease (PD) is the loss of the dopaminergic nigrostriatal pathway which lies at the heart of many of the motor... (Review)
Review
One of the core pathological features of Parkinson's disease (PD) is the loss of the dopaminergic nigrostriatal pathway which lies at the heart of many of the motor features of this condition as well as some of the cognitive problems. The importance of this pathological event is evident through the clinical benefits that are seen when patients with PD are treated with dopaminergic agents, at least in early-stage disease. However, these agents create problems of their own through stimulation of more intact dopaminergic networks within the central nervous system causing major neuropsychiatric problems including dopamine dysregulation. In addition, over time the nonphysiological stimulation of striatal dopamine receptors by l-dopa containing drugs leads to the genesis of l-dopa-induced dyskinesias that can become very disabling in many cases. As such, there has been much interest in trying to better reconstitute the dopaminergic nigrostriatal pathway using either factors to regrow it, cells to replace it, or gene therapies to restore dopamine transmission in the striatum. In this chapter, we lay out the rationale, history and current status of these different therapies as well as highlighting where the field is heading and what new interventions might come to clinic in the coming years.
Topics: Humans; Parkinson Disease; Levodopa; Dopamine; Corpus Striatum; Central Nervous System
PubMed: 36803812
DOI: 10.1016/B978-0-323-85555-6.00012-6