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Trends in Molecular Medicine Jun 2024Innovative therapeutic strategies are urgently needed for Parkinson's disease due to limited efficacy of current treatments and a weak therapeutic pipeline. In this...
Innovative therapeutic strategies are urgently needed for Parkinson's disease due to limited efficacy of current treatments and a weak therapeutic pipeline. In this forum article, we propose targeting tyrosine hydroxylase phosphorylation as a novel mechanism of action to address this critical need.
PubMed: 38926032
DOI: 10.1016/j.molmed.2024.06.002 -
The Journal of Organic Chemistry Jun 2024This report describes a Pd-catalyzed picolinamide-directed site-selective C(sp)-H sulfonylation of amino acids and peptides with sodium sulfinates in moderate to good...
This report describes a Pd-catalyzed picolinamide-directed site-selective C(sp)-H sulfonylation of amino acids and peptides with sodium sulfinates in moderate to good yields. Sulfonylation of levodopa and dopamine drug molecules and late-stage directed peptide sulfonylation are studied for the first time. Broad substrate scope having various functionalities, late-stage drug modifications, and various post synthetic utilities such as chalcogenation, bromination, olefination, and arylation are potential advantages.
PubMed: 38924796
DOI: 10.1021/acs.joc.4c00988 -
Motor Efficacy of Subcutaneous DIZ102, Intravenous DIZ101 or Intestinal Levodopa/Carbidopa Infusion.Movement Disorders Clinical Practice Jun 2024It has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and...
BACKGROUND
It has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and blocking central levodopa conversion to dopamine. We previously demonstrated equivalent plasma levodopa concentration in patients with Parkinson's disease during 16 h of (1) intravenous carbidopa/levodopa (DIZ101) infusion, (2) subcutaneous carbidopa/levodopa (DIZ102) infusion or (3) intestinal carbidopa/levodopa gel infusion. Plasma levels of carbidopa were however approximately four times higher with DIZ101 and DIZ102 than with LCIG, and higher than those usually observed with oral levodopa/carbidopa.
OBJECTIVES
To investigate if high carbidopa blood concentrations obtained with parenteral levodopa/carbidopa (ratio 8:1) counter the effect of levodopa on motor symptoms.
METHODS
Eighteen patients with advanced Parkinson's disease were administered DIZ101, DIZ102, and intestinal levodopa/carbidopa gel for 16 h on different days in randomized order. Video recordings of a subset of the motor examination in the Unified Parkinson's Disease Rating Scale (UPDRS) were evaluated by raters blinded for treatment and time. Motor function was also measured using a wrist-worn device monitoring bradykinesia, dyskinesia, and tremor (Parkinson KinetiGraph).
RESULTS
There was no tendency for poorer levodopa effect with DIZ101 or DIZ102 as compared to LCIG.
CONCLUSION
Although DIZ101 or DIZ102 causes approximately four times higher plasma carbidopa levels than LCIG, patients responded equally well to all treatments. The results do not indicate that high plasma carbidopa levels hamper the motor efficacy of levodopa.
PubMed: 38924339
DOI: 10.1002/mdc3.14138 -
Analytical Methods : Advancing Methods... Jun 2024Pteridines are important low molecular weight biomarkers used in the diagnostics of inflammation, oxidative stress, phenylketonuria, cancer, In this experimental study,...
Pteridines are important low molecular weight biomarkers used in the diagnostics of inflammation, oxidative stress, phenylketonuria, cancer, In this experimental study, we present a simple and selective approach to determine pteridines (pterin, leucopterin and folic acid) and nucleobase guanine concentration using luminescent gold clusters stabilized by aromatic amino acids. We synthesized several new gold clusters (AA-Au NCs) stabilized by various aromatic amino acids - 3,4-dihydroxy-L-phenylalanine (DOPA), L-tryptophan (Trp), L-tyrosine (Tyr) and L-phenylalanine (Phe), emitting in the violet-green spectral range. Their luminescence appeared to be sensitive to the presence of pterin, leucopterin, folic acid and guanine depending on the stabilizing matrix. Thus, a facile and cost-effective approach for the detection of pteridines is proposed. AA-Au NC-based sensors work according to "turn-off" and "turn-on" mechanisms. The possible physical origins of their luminescence quenching and enhancement are discussed.
PubMed: 38920251
DOI: 10.1039/d4ay00700j -
Mini Reviews in Medicinal Chemistry Jun 2024Parkinson's Disease (PD) is the most common neurodegenerative disorder after Alzheimer's Disease and is clinically expressed by movement disorders, such as tremor,...
Parkinson's Disease (PD) is the most common neurodegenerative disorder after Alzheimer's Disease and is clinically expressed by movement disorders, such as tremor, bradykinesia, and rigidity. It occurs mainly in the extrapyramidal system of the brain and is characterized by dopaminergic neuron degeneration. L-DOPA, dopaminergic agonists, anticholinergic drugs, and MAO-B inhibitors are currently used as therapeutic agents against PD, however, they have only symptomatic efficacy, mainly due to the complex pathophysiology of the disease. This review summarizes the main aspects of PD pathology, as well as, discusses the most important biochemical dysfunctions during PD, and presents novel multi-targeting compounds, which have been tested for their activity against various targets related to PD. This review selects various research articles from main databases concerning multi-targeting compounds against PD. Molecules targeting more than one biochemical pathway involved in PD, expected to be more effective than the current treatment options, are discussed. A great number of research groups have designed novel compounds following the multi-targeting drug approach. They include structures combining antioxidant, antiinflammatory, and metal-chelating properties. These compounds could be proven useful for effective multi-targeted PD treatment. Multi-targeting drugs could be a useful tool for the design of effective antiparkinson agents. Their efficacy towards various targets implicated in PD could be the key to the radical treatment of this neurodegenerative disorder.
PubMed: 38918988
DOI: 10.2174/0113895575303788240606054620 -
Brain : a Journal of Neurology Jun 2024Pain is a non-motor symptom that impairs quality of life in Parkinson's patients. Pathological nociceptive hypersensitivity in patients could be due to changes in the...
BACKGROUND
Pain is a non-motor symptom that impairs quality of life in Parkinson's patients. Pathological nociceptive hypersensitivity in patients could be due to changes in the processing of somatosensory information at the level of the basal ganglia, including the subthalamic nucleus (STN), but the underlying mechanisms are not yet defined. Here, we investigated the interaction between the STN and the dorsal horn of the spinal cord (DHSC), by first examining the nature of STN neurons that respond to peripheral nociceptive stimulation and the nature of their responses under normal and pathological conditions. Next, we studied the consequences of deep brain stimulation (DBS) of the STN on the electrical activity of DHSC neurons. Then, we investigated whether the therapeutic effect of STN-DBS would be mediated by the brainstem descending pathway involving the rostral ventromedial medulla (RVM). Finally, to better understand how the STN modulates allodynia, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) expressed in the STN.
METHODS
The study was carried out on the 6-OHDA rodent model of Parkinson's disease, obtained by stereotactic injection of the neurotoxin into the medial forebrain bundle of rats and mice. In these animals, we used motor and nociceptive behavioral tests, in vivo electrophysiology of STN and wide dynamic range (WDR) DHSC neurons in response to peripheral stimulation, deep brain stimulation of the STN and the selective DREADD approach. Vglut2-ires-cre mice were used to specifically target and inhibit STN glutamatergic neurons.
RESULTS
STN neurons are able to detect nociceptive stimuli, encode their intensity and generate windup-like plasticity, like WDR neurons in the DHSC. These phenomena are impaired in dopamine-depleted animals, as the intensity response is altered in both spinal and subthalamic neurons. Furthermore, As with L-Dopa, STN-DBS in rats ameliorated 6-OHDA-induced allodynia, and this effect is mediated by descending brainstem projections leading to normalization of nociceptive integration in DHSC neurons. Furthermore, this therapeutic effect was reproduced by selective inhibition of STN glutamatergic neurons in Vglut2-ires-cre mice.
CONCLUSION
Our study highlights the centrality of the STN in nociceptive circuits, its interaction with the DHSC and its key involvement in pain sensation in Parkinson's disease. Furthermore, our results provide for the first-time evidence that subthalamic DBS produces analgesia by normalizing the responses of spinal WDR neurons via descending brainstem pathways. These effects are due to direct inhibition, rather than activation of glutamatergic neurons in the STN or passage fibers, as shown in the DREADDs experiment.
PubMed: 38916480
DOI: 10.1093/brain/awae200 -
ACS Applied Bio Materials Jun 2024Laccase is an oxidase of great industrial interest due to its ability to catalyze oxidation processes of phenols and persistent organic pollutants. However, it is...
Laccase is an oxidase of great industrial interest due to its ability to catalyze oxidation processes of phenols and persistent organic pollutants. However, it is susceptible to denaturation at high temperatures, sensitive to pH, and unstable in the presence of high concentrations of solvents, which is a issue for industrial use. To solve this problem, this work develops the synthesis in an aqueous medium of a new Mn metalloenzyme with laccase oxidase mimetic catalytic activity. lipase (GTL) was used as a scaffold enzyme, mixed with a manganese salt at 50 °C in an aqueous medium. This leads to the in situ formation of manganese(IV) oxide nanowires that interact with the enzyme, yielding a GTL-Mn bionanohybrid. On the other hand, its oxidative activity was evaluated using the ABTS assay, obtaining a catalytic efficiency 300 times higher than that of laccase. This new Mn metalloenzyme was 2 times more stable at 40 °C, 3 times more stable in the presence of 10% acetonitrile, and 10 times more stable in 20% acetonitrile than Novozym 51003 laccase. Furthermore, the site-selective immobilized GTL-Mn showed a much higher stability than the soluble form. The oxidase-like activity of this Mn metalloenzyme was successfully demonstrated against other substrates, such as l-DOPA or phloridzin, in oligomerization reactions.
PubMed: 38916249
DOI: 10.1021/acsabm.4c00571 -
Revista de Neurologia Jun 2024Most patients with Parkinson's disease experience motor fluctuations or 'off' periods, which impact on their daily activities, increase their disability and diminish... (Review)
Review
Most patients with Parkinson's disease experience motor fluctuations or 'off' periods, which impact on their daily activities, increase their disability and diminish their quality of life. They suffer from these fluctuations despite multiple adjustments to the schedules, doses and intake of medication. In this context, on-demand or rescue treatments are necessary to attempt to improve 'off' periods, with drugs that have the pharmacokinetic advantage of a much faster onset of action because their routes of administration are not oral. There are currently three on-demand therapies for the treatment of fluctuations: subcutaneous apomorphine, inhaled levodopa and sublingual apomorphine. Of the three alternatives, subcutaneous apomorphine generally has the fastest onset of action, sublingual apomorphine provides the longest clinical effect, and inhaled levodopa has the most favourable side effect profile. Each of these drugs has its own characteristics: the time before onset of action, the duration of action and different side effect profiles. The choice for each patient will depend on their individual needs and circumstances. To mark the first year of the introduction of inhaled levodopa, we review these therapies, focusing on the experience with this new dosage form of levodopa.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Administration, Inhalation; Apomorphine
PubMed: 38916176
DOI: 10.33588/rn.78S01.2024196 -
JCEM Case Reports Jun 2024Pheochromocytomas predominantly produce catecholamines, and rarely also produce ACTH, causing Cushing syndrome (CS). Cyclic CS, an uncommon presentation of...
Pheochromocytomas predominantly produce catecholamines, and rarely also produce ACTH, causing Cushing syndrome (CS). Cyclic CS, an uncommon presentation of hypercortisolism, poses a diagnostic challenge. We report a 71-year-old woman who developed cyclic ectopic ACTH secretion from a pheochromocytoma. Previous evaluations showed intermittent elevations in cortisol and ACTH levels, normal pituitary magnetic resonance imaging, and an adrenal nodule. On admission, she was hypertensive and had cushingoid features. Bilateral inferior petrosal sinus sampling with desmopressin stimulation and an 8-mg dexamethasone suppression test suggested ectopic ACTH secretion, but ACTH increased during the peripheral desmopressin stimulation test. Plasma normetanephrines were about 2-fold above the upper reference limit. F-fluoro-dopa and Gallium-DOTATATE positron emission tomography/computed tomography scans, computed tomography, and magnetic resonance imaging identified an adrenal mass. After doxazosin adrenoceptor blockade, she underwent right adrenalectomy; histopathology and immunohistochemistry confirmed an ACTH-secreting pheochromocytoma. Postoperative blood pressure normalized and serum cortisol and plasma ACTH levels were suppressed, requiring physiologic hydrocortisone replacement. This case underscores the importance of considering pheochromocytoma in ACTH-dependent hypercortisolism with elevated metanephrines and an adrenal mass. Timely diagnosis and treatment can reduce morbidity and improve quality of life.
PubMed: 38915761
DOI: 10.1210/jcemcr/luae094 -
Frontiers in Aging Neuroscience 2024Patients with Parkinson's disease (PD) exhibit a heightened risk of falls and related fractures compared to the general population. This study aims to assess the...
BACKGROUND
Patients with Parkinson's disease (PD) exhibit a heightened risk of falls and related fractures compared to the general population. This study aims to assess the clinical characteristics associated with falls in the patient with PD and to gain further insight into these factors through Mendelian randomization analysis.
METHODS
From January 2013 to December 2023, we included 591 patients diagnosed with Parkinson's disease at Shenzhen Baoan People's Hospital. Using univariate and multivariate logistic regression analyses, we identified clinical variables associated with falls. We constructed a nomogram based on these variables and evaluated the predictive efficacy of the model. Additionally, we employed summary statistics from genome-wide association studies to conduct two-sample Mendelian randomization (MR) analyses on key variables influencing falls.
RESULTS
Compared to the control group, we identified osteoporosis, motor dysfunction, higher Hoehn and Yahr scale as significant risk factors for falls in PD patients. Conversely, treatment with levodopa and a higher level of education exhibited a protective effect against the risk of falling. MR analysis further confirmed a causal relationship between osteoporosis, education level and falls in PD patients.
CONCLUSION
Osteoporosis and educational attainment are correlated with falls in Parkinson's disease.
PubMed: 38915347
DOI: 10.3389/fnagi.2024.1420885