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Journal of Biomedical Optics Jul 2012We describe the auto-oxidation of 3, 4-dihydroxy-L-phenylalanine (L-DOPA) in the synthesis of eumelanin to spontaneously produce fibrils upon drying. The self-assembled...
We describe the auto-oxidation of 3, 4-dihydroxy-L-phenylalanine (L-DOPA) in the synthesis of eumelanin to spontaneously produce fibrils upon drying. The self-assembled fibrils are of characteristic diameter ∼1 to 2 μm, composed of filaments, and are unidirectional, apart from branches that are formed at typically an angle of 20 to 22 deg. The fibrils are characterized using fluorescence spectroscopy, fluorescence decay times, scanning electron microscopy, atomic force microscopy, and fluorescence lifetime imaging microscopy. The fibrils mimic natural melanin in consisting of core eumelanin with efficient nonradiative properties, but they also display pockets of electronically isolated species with higher radiative rates on the nanosecond timescale. Eumelanin fibrils formed occasionally in solution are tentatively attributed to a scaffold of bacteria or fungus. Fabricating and characterizing novel synthetic eumelanin structures such as fibrils are of interest in helping to reveal a functional structure for eumelanin, in understanding its photophysics, in learning more about L-DOPA as it is used in the treatment of Parkinson's disease, and in producing novel materials which might embody some of the diverse properties of eumelanin.
Topics: Biomimetic Materials; Levodopa; Macromolecular Substances; Materials Testing; Melanins; Microscopy, Electron; Molecular Conformation; Oxidation-Reduction; Spectrum Analysis
PubMed: 22894473
DOI: 10.1117/1.JBO.17.7.075001 -
Biosensors Feb 2022Levodopa (L-Dopa) is considered to be one of the most effective therapies available for Parkinson's disease (PD) treatment. The therapeutic window of L-Dopa is narrow...
Levodopa (L-Dopa) is considered to be one of the most effective therapies available for Parkinson's disease (PD) treatment. The therapeutic window of L-Dopa is narrow due to its short half-life, and long-time L-Dopa treatment will cause some side effects such as dyskinesias, psychosis, and orthostatic hypotension. Therefore, it is of great significance to monitor the dynamic concentration of L-Dopa for PD patients with wearable biosensors to reduce the risk of complications. However, the high concentration of interferents in the body brings great challenges to the in vivo monitoring of L-Dopa. To address this issue, we proposed a minimal-invasive L-Dopa biosensor based on a flexible differential microneedle array (FDMA). One working electrode responded to L-Dopa and interfering substances, while the other working electrode only responded to electroactive interferences. The differential current response of these two electrodes was related to the concentration of L-Dopa by eliminating the common mode interference. The differential structure provided the sensor with excellent anti-interference performance and improved the sensor's accuracy. This novel flexible microneedle sensor exhibited favorable analytical performance of a wide linear dynamic range (0-20 μM), high sensitivity (12.618 nA μM cm) as well as long-term stability (two weeks). Ultimately, the L-Dopa sensor displayed a fast response to in vivo L-Dopa dynamically with considerable anti-interference ability. All these attractive performances indicated the feasibility of this FDMA for minimal invasive and continuous monitoring of L-Dopa dynamic concentration for Parkinson's disease.
Topics: Biosensing Techniques; Electrodes; Humans; Levodopa; Parkinson Disease; Wearable Electronic Devices
PubMed: 35200363
DOI: 10.3390/bios12020102 -
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 -
Movement Disorders : Official Journal... Jan 2015Levodopa (L-dopa) has been at the forefront of antiparkinsonian therapy for a half century. Recent advances in functional brain imaging have contributed substantially to... (Review)
Review
Levodopa (L-dopa) has been at the forefront of antiparkinsonian therapy for a half century. Recent advances in functional brain imaging have contributed substantially to the understanding of the effects of L-dopa and other dopaminergic treatment on the activity of abnormal motor and cognitive brain circuits in Parkinson's disease patients. Progress has also been made in understanding the functional pathology of dyskinesias, a common side effect of l-dopa treatment, at both regional and network levels. Here, we review these studies, focusing mainly on the new mechanistic insights provided by metabolic brain imaging and network analysis.
Topics: Animals; Antiparkinson Agents; Cerebral Cortex; Cognition Disorders; Humans; Levodopa; Neuroimaging; Parkinson Disease; Regional Blood Flow
PubMed: 25296957
DOI: 10.1002/mds.26041 -
BMC Medicine Oct 2022Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal...
BACKGROUND
Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal models and medications await development to elucidate the aetiology of PD and attenuate the symptoms, respectively.
METHODS
A neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was used in the current study to establish a PD pathologic model in silkworms. The time required to complete specific behaviours was recorded. Dopamine content was detected by ultra-performance liquid chromatography (UPLC). The activity of insect tyrosine hydroxylase (TH) was determined using a double-antibody sandwich method. Oxidative stress was assessed by changes in antioxidant enzyme activity and the content of oxidative products.
RESULTS
MPTP-treated silkworms were characterized by impaired motor ability, reduced dopamine content, and elevated oxidative stress level. The expression of TH, a dopamine biosynthetic enzyme within dopaminergic neurons in the brain, was significantly reduced, indicating that dopaminergic neurons were damaged. Moreover, MPTP-induced motility impairment and reduced dopamine level in the silkworm PD model could be rescued after feeding a combination of levodopa (L-dopa [LD]) and carbidopa (CD). MPTP-induced oxidative damage was also alleviated, in ways consistent with other PD animal models. Interestingly, administration of Lycium barbarum polysaccharide (LBP) improved the motor ability, dopamine level, and TH activity, and the oxidative damage was concomitantly reduced in the silkworm PD model.
CONCLUSIONS
This study provides a promising animal model for elucidating the pathogenesis of PD, as well as a relevant preliminary drug screening (e.g., LBP) and evaluation.
Topics: Animals; Mice; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Antioxidants; Disease Models, Animal; Dopamine; Levodopa; Mice, Inbred C57BL; Tyrosine 3-Monooxygenase; Parkinson Disease, Secondary; Drugs, Chinese Herbal
PubMed: 36303171
DOI: 10.1186/s12916-022-02621-9 -
Journal of Nuclear Medicine : Official... Jul 2021Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The...
Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The clinical course varies from mild to severe, with a significant risk for brain damage. Imaging plays a valuable role in the care of infants and children with severe hypoglycemia unresponsive to medical therapy. F-6-fluoro-l-dopa PET/CT is the method of choice for the detection and localization of a focal lesion of hyperinsulinism. Surgical resection of a focal lesion can lead to a cure with limited pancreatectomy. This article reviews the role of F-6-fluoro-l-dopa PET/CT in the management of this vulnerable population.
Topics: Congenital Hyperinsulinism; Humans; Infant; Levodopa; Positron Emission Tomography Computed Tomography
PubMed: 34230074
DOI: 10.2967/jnumed.120.246033 -
Cell Metabolism Aug 2019Levodopa (L-dopa) is the primary treatment for Parkinson's disease. The gut microbiome can metabolize levodopa, potentially leading to decreased efficacy and side...
Levodopa (L-dopa) is the primary treatment for Parkinson's disease. The gut microbiome can metabolize levodopa, potentially leading to decreased efficacy and side effects, but responsible bacteria were unknown. Maini Rekdal et al. (2019) characterize enzymes in two gut bacteria that sequentially metabolize L-dopa and identify a novel inhibitor that may improve outcomes.
Topics: Bacteria; Gastrointestinal Microbiome; Humans; Levodopa; Parkinson Disease
PubMed: 31390549
DOI: 10.1016/j.cmet.2019.07.005 -
Neuroscience and Biobehavioral Reviews Jan 2011Though the most recognizable symptoms of Parkinson's disease (PD) are motor-related, many patients also suffer from debilitating affective symptoms that deleteriously... (Review)
Review
Though the most recognizable symptoms of Parkinson's disease (PD) are motor-related, many patients also suffer from debilitating affective symptoms that deleteriously influence quality of life. Dopamine (DA) loss is likely involved in the onset of depression and anxiety in PD. However, these symptoms are not reliably improved by DA replacement therapy with l-3,4-dihydroxyphenylalanine (l-DOPA). In fact, preclinical and clinical evidence suggests that l-DOPA treatment may worsen affect. Though the neurobiological mechanisms remain unclear, recent research contends that l-DOPA further perturbs the function of the norepinephrine and serotonin systems, already affected by PD pathology, which have been intimately linked to the development and expression of anxiety and depression. As such, this review provides an overview of the clinical characteristics of affective disorders in PD, examines the utility of animal models for the study of anxiety and depression in PD, and finally, discusses potential mechanisms by which DA loss and subsequent l-DOPA therapy influence monoamine function and concomitant affective symptoms.
Topics: Animals; Antiparkinson Agents; Anxiety; Depression; Disease Models, Animal; Humans; Levodopa; Neurotransmitter Agents; Parkinson Disease
PubMed: 20615430
DOI: 10.1016/j.neubiorev.2010.06.007 -
Molecular Medicine Reports Mar 2021The dopamine precursor 3,4‑dihydroxyphenyl‑ l‑alanine (L‑DOPA) is the most widely used symptomatic treatment for Parkinson's disease (PD); however, its prolonged...
The dopamine precursor 3,4‑dihydroxyphenyl‑ l‑alanine (L‑DOPA) is the most widely used symptomatic treatment for Parkinson's disease (PD); however, its prolonged use is associated with L‑DOPA‑induced dyskinesia in more than half of patients after 10 years of treatment. The present study investigated whether co‑treatment with β‑Lapachone, a natural compound, and L‑DOPA has protective effects in a 6‑hydroxydopamine (6‑OHDA)‑induced mouse model of PD. Unilateral 6‑OHDA‑lesioned mice were treated with vehicle or β‑Lapachone (10 mg/kg/day) and L‑DOPA for 11 days. Abnormal involuntary movements (AIMs) were scored on days 5 and 10. β‑Lapachone (10 mg/kg) co‑treatment with L‑DOPA decreased the AIMs score on both days 5 and 10. β‑Lapachone was demonstrated to have a beneficial effect on the axial and limb AIMs scores on day 10. There was no significant suppression in dopamine D1 receptor‑related and ERK1/2 signaling in the DA‑denervated striatum by β‑Lapachone‑cotreatment with L‑DOPA. Notably, β‑Lapachone‑cotreatment with L‑DOPA increased phosphorylation at the Ser9 site of glycogen synthase kinase 3β (GSK‑3β), indicating suppression of GSK‑3β activity in both the unlesioned and 6‑OHDA‑lesioned striata. In addition, astrocyte activation was markedly suppressed by β‑Lapachone‑cotreatment with L‑DOPA in the striatum and substantia nigra of the unilateral 6‑OHDA model. These findings suggest that β‑Lapachone cotreatment with L‑DOPA therapy may have therapeutic potential for the suppression or management of the development of L‑DOPA‑induced dyskinesia in patients with PD.
Topics: Animals; Dyskinesias; Levodopa; Male; Mice; Naphthoquinones; Oxidopamine; Parkinson Disease, Secondary
PubMed: 33495840
DOI: 10.3892/mmr.2021.11856 -
PloS One 2022Simultaneous imaging of l-dihydroxyphenylalanine (l-DOPA), dopamine (DA) and norepinephrine (NE) in the catecholamine metabolic pathway is particularly useful because...
Simultaneous imaging of l-dihydroxyphenylalanine (l-DOPA), dopamine (DA) and norepinephrine (NE) in the catecholamine metabolic pathway is particularly useful because l-DOPA is a neurophysiologically important metabolic intermediate. In this study, we found that 2,4,6-trimethylpyrillium tetrafluoroborate (TMPy) can selectively and efficiently react with target catecholamine molecules. Specifically, simultaneous visualization of DA and NE as metabolites of l-DOPA with high steric hinderance was achieved by derivatized-imaging mass spectrometry (IMS). Interestingly, l-DOPA showed strong localization in the brainstem, in contrast to the pattern of DA and NE, which co-localized with tyrosine hydroxylase (TH). In addition, to identify whether the detected molecules were endogenous or exogenous l-DOPA, mice were injected with l-DOPA deuterated in three positions (D3-l-DOPA), which was identifiable by a mass shift of 3Da. TMPy-labeled l-DOPA, DA and NE were detected at m/z 302.1, 258.1 and 274.1, while their D3 versions were detected at 305.0, 261.1 and 277.1 in mouse brain, respectively. l-DOPA and D3-l-DOPA were localized in the BS. DA and NE, and D3-DA and D3-NE, all of which are metabolites of L-DOPA and D3-l-DOPA, were localized in the striatum (STR) and locus coeruleus (LC). These findings suggest a mechanism in the brainstem that allows l-DOPA to accumulate without being metabolized to monoamines downstream of the metabolic pathway.
Topics: Animals; Catecholamines; Dopamine; Levodopa; Mass Spectrometry; Mice; Norepinephrine
PubMed: 35917331
DOI: 10.1371/journal.pone.0271697