Catecholamine Neurotransmitters Research Articles

The Catechol O-MethyltransferaseInhibitor Entacapone in the Treatment of Parkinson's Disease: Personal Reflections on a First-in-Class Drug Development Programme 40Years On.

In the 1980s, Orion Pharma, then a mid-ranking Nordic area pharmaceutical company, established a drug development programme on the inhibition of catechol O-methyltransferase (COMT). This enzyme, which plays an important role in the inactivation of catecholamine neurotransmitters and drugs with a catechol structure, thus came under consideration as a target in the innovative translational and clinical programme we describe in this historical review. The starting point was the conjecture that a peripherally acting COMT inhibitor might improve entry of levodopa into the brain. This had potentially significant implications for the medical treatment of Parkinson's disease (PD). The rationale was that more efficient delivery of levodopa to the brain might allow the high therapeutic doses of levodopa to be reduced and the dose interval to be extended. Elucidation of structure-activity relations paved the way for the discovery and development of entacapone, a 5-nitrocatechol that was a potent and highly specific inhibitor of COMT. Experience in phaseIII clinical trials established that entacapone, used as an adjunct to regular or controlled-release levodopa preparations (also including a peripherally acting dopa-decarboxylase inhibitor), increased ON-time and reduced OFF-time and improved clinical condition in patients with PD experiencing wearing-off, often with a reduced daily levodopa dose. Several of these studies also identified that entacapone improved patients' quality of life and was cost-effective. Subsequently, entacapone has been amalgamated into a triple-combination preparation (Stalevo®) with levodopa and carbidopa to create a flexible and convenient drug therapy for patients with PD who have end-of-dose motor fluctuations not stabilised on levodopa/dopa-decarboxylase inhibitor treatment. This review offers a historical perspective on a successful programme of drug development by researchers who played central roles in the progress from exploratory hypothesis to registered pharmaceutical product.

Smartphone-Based Sensing of Cortisol by Functionalized Rhodamine Probes.

During a stress condition, the human body synthesizes catecholamine neurotransmitters and specific hormones (called "stress hormones"), the most important of which is cortisol. The monitoring of cortisol levels should be extremely important to control the stress levels, and for this reason, it shows important medical applications. The common analytical methods (HPLC, GC-MS) cannot be used in real life, due to the bulky size of the instruments and the necessity of specialized personnel. Molecular probes solve these problems due to their fast and easy use. The synthesis of new fluorescent rhodamine probes, able to interact by non-covalent interactions with cortisol, the recognition properties in solution as well as in solid state by Strip Test, using a smartphone as detector, are here reported. DFT calculations and FT-IR measurements suggest the formation of supramolecular complexes through hydrogen bonds as main non-covalent interaction. The present study represents one of the first sensor, based on synthetical chemical receptors, able to detect cortisol in a linear range from 1 mM to 1 pM, based on non-covalent molecular recognition and paves the way to the realization of practical point-of-care device for the monitoring of cortisol in real live.

Immobilization of human tyrosine hydroxylase onto magnetic nanoparticles – A novel formulation of a therapeutic enzyme

Human tyrosine hydroxylase (hTH) has key role in the production of catecholamine neurotransmitters. The structure, function and regulation of hTH has been extensively researched area and the possibility of enzyme replacement therapy (ERT) involving hTH through nanocarriers has been raised as well. However, our understanding on how hTH may interact with nanocarriers is still lacking. In this work, we attempted to investigate the immobilization of hTH on magnetic nanoparticles (MNPs) with various surface linkers in quantitative and mechanistic detail. Our results showed that the activity of hTH was retained after immobilization via secondary and covalent interactions as well. The colloidal stability of hTH could be also enhanced proved by Dynamic light scattering and Zeta potential analysis and a homogenous enzyme layer could be achieved, which was investigated by Raman mapping. The covalent attachment of hTH on MNPs via aldehyde or epoxy linkers provide irreversible immobilization and 38.1 % and 16.5 % recovery (ER). The hTH-MNPs catalyst had 25 % ER in average in simulated nasal electrolyte solution (SNES). This outcome highlights the relevance of immobilization applying MNPs as a potential formulation tool of sensitive therapeutic enzymes offering new opportunities for ERT related to neurodegenerative disorders.

An electrochemical sensor based on a modified glassy carbon electrode for detection of epinephrine in the presence of theophylline.

Neurotransmitters are chemical messengers that enhance and balance signals between cells and target cells in the body. They are vital to the body's ability to function. Epinephrine is one of the most essential catecholamine neurotransmitters with an important biological and pharmacological role in the mammalian central nervous system. Therefore, it is very important to develop sensitive, simple, and fast methods for the determination of this compound. In the present work, a glassy carbon electrode (GCE) modified with the cerium oxide-zinc oxide (CeO2-ZnO) nanocomposite (CeO2-ZnO/GCE) was developed for the sensitive and quick detection of epinephrine. The CeO2-ZnO nanocomposite was prepared by hydrothermal method. Electrochemical methods such as voltammetry and chronoamperometry techniques were used to investigate the performance of the developed sensor. The resulting CeO2-ZnO/GCE showed a remarkable response towards the determination of epinephrine. The electrochemical sensor demonstrated a wide dynamic linear range from 0.1 to 900.0 μM for analysis of epinephrine. The LOD equalled 0.03 μM for epinephrine. In addition, the electrochemical sensor had good feasibility for concurrent detection of epinephrine and theophylline. Furthermore, experimental outputs indicated that the oxidation peaks of epinephrine and theophylline were separated by a 685 mV difference between the two peaks in PBS at a pH of 7.0. Also, an electrochemical sensor has been employed to analyse epinephrine in real samples (urine and epinephrine Injection). The good and acceptable analytical performance of the developed sensor can provide a promising tool for the analysis of epinephrine in real samples.

Integrated omics approach reveals the molecular pathways activated in tomato by Kocuria rhizophila, a soil plant growth-promoting bacterium

Plant microbial biostimulants application has become a promising and eco-friendly agricultural strategy to improve crop yields, reducing chemical inputs for more sustainable cropping systems. The soil dwelling bacterium Kocuria rhizophila was previously characterized as Plant Growth Promoting Bacteria (PGPB) for its multiple PGP traits, such as indole-3-acetic acid production, phosphate solubilization capability and salt and drought stress tolerance. Here, we evaluated by a multi-omics approach, the PGP activity of K. rhizophila on tomato, revealing the molecular pathways by which it promotes plant growth. Transcriptomic analysis showed several up-regulated genes mainly related to amino acid metabolism, cell wall organization, lipid and secondary metabolism, together with a modulation in the DNA methylation profile, after PGPB inoculation. In agreement, proteins involved in photosynthesis, cell division, and plant growth were highly accumulated by K. rhizophila. Furthermore, “amino acid and peptides”, “monosaccharides”, and “TCA” classes of metabolites resulted the most affected by PGPB treatment, as well as dopamine, a catecholamine neurotransmitter mediating plant growth through S-adenosylmethionine decarboxylase (SAMDC), a gene enhancing the vegetative growth, up-regulated in tomato by K. rhizophila treatment. Interestingly, eight gene modules well correlated with differentially accumulated proteins (DAPs) and metabolites (DAMs), among which two modules showed the highest correlation with nine proteins, including a nucleoside diphosphate kinase, and cytosolic ascorbate peroxidase, as well as with several amino acids and metabolites involved in TCA cycle. Overall, our findings highlighted that sugars and amino acids, energy regulators, involved in tomato plant growth, were strongly modulated by the K. rhizophila-plant interaction.

Colorimetric Sensor Array for Simultaneous Assay of Catecholamine Neurotransmitters Using Various-Sized Citrate-Capped Gold Nanoparticles

Driven by the need to in situ monitoring of the endogenous substances in biological matrices, a simple, rapid and sensitive optical nanoarray system has been designed for determination and visual discrimination of four important catecholamine neurotransmitters: dopamine (DA), epinephrine (EP), norepinephrine (NE) and levodopa (LD). To fabricate this platform, spherical citrate-capped gold nanoparticles (AuNPs) in the size range of 13–42 nm have been employed as sensing elements. For each catecholamine different responses toward the AuNPs was obtained indicating unique aggregation kinetics. When the sensor array exposed to different catecholamines (CAs), both the color and UV–Vis absorbance spectra changed due to the interaction of analytes and AuNPs, creating a unique fingerprint-like pattern for each analyte which can be visually detected by naked eye. To analyze response profiles, we employed unsupervised chemometric algorithms including hierarchical cluster analysis (HCA) and principal component analysis (PCA) and satisfactory class separations were achieved. Furthermore, the sensitive RGB based color difference patterns were generated providing easily monitored visual output. Based on this sensor array, the set of four catecholamine neurotransmitters have been correctly identified and classified in the spiked real urine samples. The target analytes have been well distinguished at low concentrations of 0.3 − 4 μM DA, 0.8 − 10 μM EP, 0.8 − 8 μM NE, and 0.3 − 10 μM LD using the proposed “chemical nose” strategy. We believe that the established optical sensor array can be potentially employed as an efficient discrimination tool for diagnostic and therapeutic applications in the future.

Disposable paper electrodes for detection of changes in dopamine concentrations in rat brain homogenates

Dopamine, the main catecholamine neurotransmitter plays an important role in renal, cardiovascular, central nervous systems, and pathophysiological processes. The abnormal dopamine levels can result in neurological disorders such as Parkinson's, Alzheimer's, schizophrenia, acute anxiety, neuroblastoma and also contribute to cognitive dysfunctions. Given the widespread importance of dopamine concentration levels, it is imperative to develop sensors that are able to monitor dopamine. Herein, we have developed pre-anodized disposable paper electrode modified with 1-pyrenebutyric acid, for the selective and sensitive determination of dopamine. The sensor was characterized with Fourier transform infrared spectroscopy, Energy dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, and electrochemical techniques for addressing the robust formation and electrochemical activity. The modified electrode exhibited excellent electrocatalytic activity towards dopamine without the common interference from ascorbic acid. The calibration plot for the dopamine sensor resulted linear range from 0.003 μM to 0.5 μM with a detection limit of 0.11 nM. The sensor's potential utility was tested by monitoring dopamine concentration changes in rat brain homogenates when subjected to neurotoxicity. The developed sensor was validated with gold-standard UV–Vis spectroscopy studies and computational studies were performed to understand the interaction between 1-pyrenebutyric acid and dopamine.

In vitro drug screening models derived from different PC12 cell lines for exploring Parkinson's disease based on electrochemical signals of catecholamine neurotransmitters.

Goldnanostructures anda Nafion modified screen-printed carbon electrode (Nafion/AuNS/SPCE) were developed to assess the cell viability of Parkinson's disease (PD) cell models. The electrochemical measurement of cell viability was reflected by catecholamine neurotransmitter (represented by dopamine) secretion capacity, followed by a traditional tetrazolium-based colorimetric assay for confirmation. Due to the capacity to synthesize, store, and release catecholamines as well as theirunlimited homogeneous proliferation, and ease of manipulation, pheochromocytoma (PC12) cells were used for PD cell modeling.Commercial low-differentiated and highly-differentiated PC12 cells, and home-made nerve growth factor (NGF) induced low-differentiated PC12 cells (NGF-differentiated PC12 cells)were included in the modeling. This approach achieved sensitive and rapid determination of cellular modeling and intervention states. Notably, among the three cell lines, NGF-differentiated PC12 cells displayed the enhanced neurotransmitter secretion level accompanied with attenuated growth rate, incremental dendrites in number and length that were highly resemble with neurons. Therefore, it was selected as the PD-tailorable modeling cell line. In short, the electrochemical sensor can be used to sensitively determine the biological function of neuron-like PC12 cells with negligible destruction and to explore the protective and regenerative impact of various substances on nerve cell model.

Ratiometric Imaging of Catecholamine Neurotransmitters with Nanosensors.

Neurotransmitters are important signaling molecules in the brain and are relevant in many diseases. Measuring them with high spatial and temporal resolutions in biological systems is challenging. Here, we develop a ratiometric fluorescent sensor/probe for catecholamine neurotransmitters on the basis of near-infrared (NIR) semiconducting single wall carbon nanotubes (SWCNTs). Phenylboronic acid (PBA)-based quantum defects are incorporated into them to interact selectively with catechol moieties. These PBA-SWCNTs are further modified with poly(ethylene glycol) phospholipids (PEG-PL) for biocompatibility. Catecholamines, including dopamine, do not affect the intrinsic E11 fluorescence (990 nm) of these (PEG-PL-PBA-SWCNT) sensors. In contrast, the defect-related E11* emission (1130 nm) decreases by up to 35%. Furthermore, this dual functionalization allows tuning selectivity by changing the charge of the PEG polymer. These sensors are not taken up by cells, which is beneficial for extracellular imaging, and they are functional in brain slices. In summary, we use dual functionalization of SWCNTs to create a ratiometric biosensor for dopamine.

Effects of Bradykinin B2 Receptor Ablation from Tyrosine Hydroxylase Cells on Behavioral and Motor Aspects in Male and Female Mice.

The kallikrein-kinin system is a versatile regulatory network implicated in various biological processes encompassing inflammation, nociception, blood pressure control, and central nervous system functions. Its physiological impact is mediated through G-protein-coupled transmembrane receptors, specifically the B1 and B2 receptors. Dopamine, a key catecholamine neurotransmitter widely distributed in the CNS, plays a crucial role in diverse physiological functions including motricity, reward, anxiety, fear, feeding, sleep, and arousal. Notably, the potential physical interaction between bradykinin and dopaminergic receptors has been previously documented. In this study, we aimed to explore whether B2R modulation in catecholaminergic neurons influences the dopaminergic pathway, impacting behavioral, metabolic, and motor aspects in both male and female mice. B2R ablation in tyrosine hydroxylase cells reduced the body weight and lean mass without affecting body adiposity, substrate oxidation, locomotor activity, glucose tolerance, or insulin sensitivity in mice. Moreover, a B2R deficiency in TH cells did not alter anxiety levels, exercise performance, or motor coordination in female and male mice. The concentrations of monoamines and their metabolites in the substantia nigra and cortex region were not affected in knockout mice. In essence, B2R deletion in TH cells selectively influenced the body weight and composition, leaving the behavioral and motor aspects largely unaffected.

To Each His Own Fear: Gender-Related Association of Anxiety, Substance Use, and Eating Disorders in a Representative Birth Cohort Sample of Young Adults with Either COMT Val158Met allele

Introduction: The role of catechol-O-methyltransferase (COMT) in catecholamine neurotransmitter metabolism has led to the investigation of variants of the corresponding gene in the etiology of different psychiatric disorders, but the results are inconclusive. Methods: We have examined the relationship between COMT Val158Met single nucleotide polymorphism (rs4680) and the occurrence of psychiatric disorders in a highly representative birth cohort sample of young adults in the Estonian Children Personality Behaviour and Health Study (original n = 1,238). The lifetime occurrence of psychiatric disorders at the age of 25 years was assessed with the Mini-International Neuropsychiatric Interview. Results: Both Val- and Met-alleles of the COMT Val158Met were associated with specific psychiatric disorders. Met-allele carriers had a significantly higher occurrence of agoraphobia (3.2% vs. 0.5%; χ² = 4.10; p < 0.05) compared to Val/Val homozygotes. Also, the occurrence of panic disorder was significantly higher in female Met-allele carriers than in Val/Val homozygote females (10.2% vs. 3.6%; χ² = 4.62 p = 0.03). In contrast, the occurrence of generalized anxiety disorder was higher in Val/Val females when compared to Met-allele carriers (12.7% vs. 6.8%; χ² = 4.16; p = 0.04). Also, female Val/Val homozygotes (15.5%) had a higher occurrence of eating disorders than Met-allele carriers (6.1%) of the COMT Val158Met polymorphism (χ² = 10.39; p = 0.002). In the whole sample, Met-allele homozygotes had a higher occurrence of alcohol use and substance use disorders than Val-allele carriers (χ² = 3.62 and 3.68, respectively; p < 0.05). Conclusion: In a regional highly birth cohort representative sample, either COMT rs4680 variant was observed in association with specific psychiatric disorders.

3-aminophenylboronic acid modified carbon nitride quantum dots as fluorescent probe for selective detection of dopamine and cell imaging

Dopamine (DA) is the most abundant catecholamine neurotransmitter in the brain and plays an extremely essential role in the physiological activities of the living organism. There is a critical need for accurately and efficiently detecting DA levels in organisms in order to reflect physiological states. Carbon nitride quantum dots (C3N4) were, in recent years, used enormously as electrochemical and fluorescence probes for the detection of metal ions, biomarkers and other environmental or food impurities due to their unique advantageous optical and electronic properties. 3-Aminophenylboronic acid (3-APBA) can specifically combine with DA through an aggregation effect, providing an effective DA detection method. In this work, 3-APBA modified carbon nitride quantum dots (3-APBA-CNQDs) were synthesized from urea and sodium citrate. The structure, chemical composition and optical properties of 3-APBA-CNQDs were investigated by XRD, TEM, UV–visible, and FT-IR spectroscopy. The addition of DA could induce fluorescence quenching of 3-APBA-CNQDs possibly through the inner filter effect (IFE). 3-APBA-CNQDs shows better selectivity and sensitivity to DA than other interfering substances. By optimizing the experiment conditions, good linearity was obtained at 0.10–51 μM DA with a low detection limit of 22.08 nM. More importantly, 3-APBA-CNQDs have been successfully applied for the detection of DA in human urine and blood samples as well as for bioimaging of intracellular DA. This study provides a promising novel method for the rapid detection of DA in real biological samples.

Self-assembly of simple Schiff base ligand into unique saddle-type [4x4] tetranuclear architecture and its application as selective voltammetric dopamine sensor in aqueous conditions

Dopamine, a crucial catecholamine neurotransmitter, plays essential roles in the operation of the central nervous system in humans. Disrupted dopamine release is associated with neurological disorders and depression, therefore monitoring of dopamine levels is imperative for preliminary disease detection. Development of sensitive and selective sensors for neurotransmitters that function under aqueous conditions is however still challenging, mostly due to the complexity of hybrid nanomaterials that are interacting with the electrode. Here we provide a coordination compound constructed from simple substrates, where subcomponent self-assembly leads to a unique, discrete [4 × 4] saddle-type complex [Cu4(L-H)4(BF4)2(MeOH)2](BF4)2, which was characterized by ESI-MS and FT-IR techniques, including single crystal X-ray diffraction. The Cu4L4 complex was subsequently used for modification of the bare Au electrode based on its accumulation on the electrode surface. The new voltammetric sensor (Au/complex) was applied for dopamine detection alone and in the presence of interfering ascorbic acid by using the Differential Pulse Voltammetry (DPV) techniques under aqueous conditions. In the linear dynamic range (LDR) range from 0.0001 mM to 0.75 mM the dependence of the peak current on dopamine concentration satisfied the following linear regression equation: ip [mA] = 17∙10−2cDA [mM] + 8∙10−2 (R2 = 0.998). Moreover, the excellent limit of dopamine detection (LOD) and the limit of its quantification (LOQ) were established at the level of 5.4 nM and 18.0 nM with accomplished high sensitivity 0.17 A M−1, repeatability as well as reproducibility. Clear separation of the voltammetric signal of dopamine from this one of ascorbic acid, even in the presence of a 100-fold excess of interfering ions found in water, consequently proves that the new prepared sensor can be used as an excellent analytical tool for selective detection of dopamine and ascorbic acid coexisting in the tested samples.

Cortisol sensing by optical sensors.

During a stress condition, the human body synthesizes catecholamine neurotransmitters and specific hormones (called "stress hormones"), the most important of which is cortisol. The monitoring of cortisol levels is extremely important for controlling the stress levels. For this reason, it has important medical applications. Common analytical methods (HPLC, GC-MS) cannot be used in real life due to the bulkiness of the instruments and the necessity of specialized operators. Molecular probes solve this problem. This review aims to provide a description of recent developments in this field, focusing on the analytical aspects and the possibility to obtain real practical devices from these molecular probes.

Assessment of the relationship between the dopaminergic pathway and severe acute respiratory syndrome coronavirus 2 infection, with related neuropathological features, and potential therapeutic approaches in COVID-19 infection.

Dopamine is a known catecholamine neurotransmitter involved in several physiological processes, including motor control, motivation, reward, cognition, and immune function. Dopamine receptors are widely distributed throughout the nervous system and in immune cells. Several viruses, including human immunodeficiency virus and Japanese encephalitis virus, can use dopaminergic receptors to replicate in the nervous system and are involved in viral neuropathogenesis. In addition, studies suggest that dopaminergic receptors may play a role in the progression and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. When SARS-CoV-2 binds to angiotensin-converting enzyme 2 receptors on the surface of neuronal cells, the spike protein of the virus can bind to dopaminergic receptors on neighbouring cells to accelerate its life cycle and exacerbate neurological symptoms. In addition, recent research has shown that dopamine is an important regulator of the immune-neuroendocrine system. Most immune cells express dopamine receptors and other dopamine-related proteins, indicating the importance of dopaminergic immune regulation. The increase in dopamine concentration during SARS-CoV2 infection may reduce immunity (innate and adaptive) that promotes viral spread, which could lead to neuronal damage. In addition, dopaminergic signalling in the nervous system may be affected by SARS-CoV-2 infection. COVID -19 can cause various neurological symptoms as it interacts with the immune system. One possible treatment strategy for COVID -19 patients could be the use of dopamine antagonists. To fully understand how to protect the neurological system and immune cells from the virus, we need to study the pathophysiology of the dopamine system in SARS-CoV-2 infection.

MicroRNA ame-let-7 targets Amdop2 to increase sucrose sensitivity in honey bees (Apis mellifera)

BackgroundAs an important catecholamine neurotransmitter in invertebrates and vertebrates, dopamine plays multiple roles in the life of the honey bee. Dopamine receptors (DA), which specifically bind to dopamine to activate downstream cascades, have been reported to be involved in honey bee reproduction, division of labour, as well as learning and motor behaviour. However, how dopamine receptors regulate honey bee behavior remains uninvestigated.ResultsThe expression level of Amdop2 in the brain increased with the age of worker bees, which was just the opposite trend of ame-let-7. Inhibition of ame-let-7 through feeding an inhibitor upregulated Amdop2 expression; conversely, overexpression of ame-let-7 through a mimic downregulated Amdop2. Moreover, knockdown of Amdop2 in forager brain led to significantly higher sucrose responsiveness, which is similar to the phenotype of overexpression of ame-let-7. Finally, we confirmed that ame-let-7 directly targets Amdop2 in vitro by a luciferase reporter assay.Conclusionsame-let-7 is involved in the dopamine receptor signaling pathway to modulate the sucrose sensitivity in honey bees. Specifically, it down-regulates Amdop2, which then induces higher responses to sucrose. These results further unraveled the diverse mechanisms of the dopamine pathway in the regulation of insect behavior.

Doping-induced assembly interface for noninvasive in vivo local and systemic immunomodulation.

Peripheral neural interfaces, potent in modulating local and systemic immune responses for disease treatment, face significant challenges due to the peripheral nerves' broad distribution in tissues like the fascia, periosteum, and skin. The incongruity between static electronic components and the dynamic, complex organization of the peripheral nervous system often leads to interface failure, stalling circuit research and clinical applications. To overcome these, we developed a self-assembling, tissue-adaptive electrode composed of a single-component cocktail nanosheet colloid, including dopants, conducting polymers, stabilizers, and an MXene catalyst. Delivered via a jet injector to designated nerve terminals, this assembly utilizes reactive oxygen species to catalytically dope poly (3,4-ethylenedioxythiophene), enhancing π-π interactions between nanosheets, and yielding a conductive, biodegradable interface. This interface effectively regulates local immune activity and promotes sensory and motor nerve functional restoration in nerve-injured mice, while engaging the vagal-adrenal axis in freely moving mice, eliciting catecholamine neurotransmitter release, and suppressing systemic cytokine storms. This innovative strategy specifically targets nerve substructures, bolstering local and systemic immune modulation, and paving the way for the development of self-adaptive dynamic neural interfaces.

SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA.

A highly selective and sensitive fluorescence probe for dopamine determination based on a bisquinoline-substituted calix[4]arene carboxylic acid derivative

Dopamine (DA) at normal levels in the human body exhibits a high potential for maintaining a proper neuron network. However, their abnormalities in humans can bring out aggressive disorders such as Schizophrenia, hypertension, Tourette’s syndrome, Alzheimer’s disease, bipolar depression, Parkinson’s disease, drug addiction and attention-deficit hyperactivity diseases. Hence, in this study, a bis-quinoline-substituted calix[4] arene carboxylic acid derivative (Quin-Calix-CO2H) at cone conformation was developed as an effective fluorescent sensor for the detection of a catecholamine neurotransmitter (dopamine). The structure of Quin-Calix-CO2H was confirmed using 1H-NMR, 13C-NMR, ESI-MS and elemental analysis techniques. The calixarene-based fluorescent sensor (Quin-Calix-CO2H) has shown fluorescence emission at 404 nm under the excitation of 270 nm. Further, biomolecules binding property of Quin-Calix-CO2H against various biomolecules such as L-cysteine (L-Cys), α-D-glucose (D-Glu), (+)-sodium-L-ascorbate (SAA), urea (UR), L-alanine (L-Ala) and dopamine (DA) exhibited that the fluorescent sensor enables selectively and sensitively detection for DA with a remarkable affinity. The probe Quin-Calix-CO2H has shown fluorescence quenching towards DA concentration ranging from 0 to 4.0 µM with a very low limit of detection (LOD) of 88.5 nmol L−1. In addition, the binding constant and stoichiometry as well as the mechanism of quenching have been also determined from the fluorescence data. Communicated by Ramaswamy H. Sarma

Stabilization and Reduced Cytotoxicity of Amyloid Beta Aggregates in the Presence of Catechol Neurotransmitters.

Oligomeric aggregates of the amyloid-beta (Aβ) peptide have been implicated as the toxic species for Alzheimer's disease by contributing to oxidative cytotoxicity and physical disruption in cell membranes in the brain. Recent evidence points to the ability of the catecholamine neurotransmitter dopamine in the presence of copper ions to both stabilize oligomers and decrease the toxic effects of these oligomers. Based on these results, physical characterization of aggregates and subsequent cell studies with a neuroblastoma line were performed that show both dopamine and the related neurotransmitter, norepinephrine, can stabilize oligomers and decrease toxicity of Aβ aggregates without copper present. To investigate this reduction of toxicity, structural characterization of oligomers in the presence of neurotransmitters was compared to aggregates formed with Aβ alone. Gel electrophoresis and transmission electron microscopy show higher levels of oligomers in the presence of dopamine and norepinephrine, yet the oligomer structure is largely amorphous. Aβ aggregated alone forms the predicted highly organized fibrillar species, with increased levels of dityrosine covalent linkages, which are largely absent in the presence of the neurotransmitters. A proposed mechanism for the observed decrease in cell death by Aβ in the presence of dopamine and norepinephrine suggests the neurotransmitters both block the formation of organized oligomer structures and dityrosine stabilizing linkages while also behaving as antioxidants, providing a dual mechanism for increased cell viability.