Dopamine Neurotransmission Research Articles

Vitamin D and Its Role on the Fatigue Mitigation: A Narrative Review.

Vitamin D has historically been associated with bone metabolism. However, over the years, a growing body of evidence has emerged indicating its involvement in various physiological processes that may influence the onset of numerous pathologies (cardiovascular and neurodegenerative diseases, rheumatological diseases, fertility, cancer, diabetes, or a condition of fatigue). This narrative review investigates the current knowledge of the pathophysiological mechanisms underlying fatigue and the ways in which vitamin D is implicated in these processes. Scientific studies in the databases of PubMed, Scopus, and Web of Science were reviewed with a focus on factors that play a role in the genesis of fatigue, where the influence of vitamin D has been clearly demonstrated. The pathogenic factors of fatigue influenced by vitamin D are related to biochemical factors connected to oxidative stress and inflammatory cytokines. A role in the control of the neurotransmitters dopamine and serotonin has also been demonstrated: an imbalance in the relationship between these two neurotransmitters is linked to the genesis of fatigue. Furthermore, vitamin D is implicated in the control of voltage-gated calcium and chloride channels. Although it has been demonstrated that hypovitaminosis D is associated with numerous pathological conditions, current data on the outcomes of correcting hypovitaminosis D are conflicting. This suggests that, despite the significant involvement of vitamin D in regulating mechanisms governing fatigue, other factors could also play a role.

Development of functionalized polymeric nanomaterial by organosiliconic reagent for boronate affinity-based dopamine recognition

The dopamine neurotransmitter is mainly responsible for endocrine functions in our body. The increase in the level of dopamine in the human body leads to many disorders such as schizophrenia, uncontrollable tics, addiction, increased tension, desire to act excessively, and carelessness. Decreased levels of dopamine cause problems such as malnutrition, stress, insomnia, and the use of antidepressants. Recognition of dopamine is crucial for clinical experiments. Therefore, the development of recognition surfaces of dopamine is essential for isolation, purification, and determination processes. This study, it was aimed to produce a polymeric nanomaterial that can recognize dopamine. For this purpose, p(HEMA) polymer was synthesized with surfactant-free emulsion polymerization method and silanized by organosilicon reagent (3-aminopropyl) triethoxylsilane (APTES) and modified with phenylboronic acid (PBA). Characterization of the p(HEMA)-APTES-PBA nanopolymeric system for dopamine recognition was performed with Scanning Electron Microscope(SEM), Energy Dispersive Spectrometry (EDS), Fourier Transform Infrared Spectroscopy (FTIR), Zeta-size/zeta-potential analysis, surface area calculations. Dopamine affinity of the p(HEMA)-APTES-PBA was optimized in terms of pH, time, concentration, buffer concentration, and buffer type parameters. Dopamine adsorption of p(HEMA)-APTES-PBA nanopolymers was 4,8 times more than epinephrine in specificity analysis. After the 7 adsorption–desorption cycles, the desorption rate was found to be 74.8 %. The developed nanopolymeric system is a convenient method with high adsorption capacity which allows easy and rapid extraction, isolation, and purification of dopamine.

Striatal dopamine neurotransmission is altered in age- and region-specific manner in a Parkinson’s disease transgenic mouse

Dopamine (DA) plays a critical role in striatal motor control. The drop in DA level within the dorsal striatum is directly associated with the appearance of motor symptoms in Parkinson’s disease (PD). The progression of the disease and inherent disruption of the DA neurotransmission has been closely related to accumulation of the synaptic protein α-synuclein. However, it is still unclear how α-synuclein affects dopaminergic terminals in different areas of dorsal striatum. Here we demonstrate that the overexpression of human α-synuclein (h-α-syn) interferes with the striatal DA neurotransmission in an age‐dependent manner, preferentially in the dorsolateral striatum (DLS) of PDGF-h-α-syn mice. While 3-month-old mice showed an increase at the onset of h-α-syn accumulation in the DLS, 12-month-old mice revealed a decrease in electrically-evoked DA release. The enhanced DA release in 3-month-old mice coincided with better performance in a behavioural task. Notably, DA amplitude alterations were also accompanied by a delay in the DA clearance independently from the animal age. Structurally, dopamine transporter (DAT) was found to be redistributed in larger DAT-positive clumps only in the DLS of 3- and 12-month-old mice. Together, our data provide new insight into the vulnerability of DLS and suggest DAT-related dysfunctionalities from the very early stages of h-α-syn accumulation.

Emerging trends on nanomaterial-based simultaneous electrochemical sensing of dopamine and acetaminophen

Recent years have witnessed significant developments in electrochemical sensing, especially voltammetric techniques, which are known for providing flexible platforms for the simultaneous measurement of the analgesic acetaminophen (AC) and the neurotransmitter dopamine (DA). The most recent advancements and trends in electrochemical methods for the simultaneous detection of these two analytes are thoroughly reviewed in this paper. The different novel electrode materials, viz. nanostructures, and several surface modifications used to improve the sensitivity, selectivity, and stability of sensors that target the electrochemistry of acetaminophen and dopamine, have been carried out in studies published in the last decade. A wide range of voltammetric techniques are covered in this investigation, such as square wave voltammetry, differential pulse voltammetry, and cyclic voltammetry. The review also critically examines the drawbacks and restrictions of the existing approaches, which range from problems with selectivity in intricate matrices to the requirement for in-vivo applications and real-time monitoring in terms of diagnostics. The pursuit of multifunctional sensors, integration of advanced nanomaterials, and standardization of experimental conditions are identified as critical research gaps. The study concludes with some notions about potential future developments, highlighting the possible influence of current trends on the advancement of electrochemical sensors for the simultaneous measurement of dopamine and acetaminophen. It also suggests future directions for ongoing research and how the exploration of unexplored areas can be attended to develop highly sensitive, selective, and cost-effective electrochemical sensors.

Au@Ag nanoparticles: an analytical tool to study the effect of tyrosine on dopamine levels.

The neurotransmitter dopamine (DA) plays important roles in the human body, including regulatory functions, movement, memory and motivational control. The direct intake of DA is impossible as it cannot cross the blood-brain barrier (BBB) efficiently. Notably, l-tyrosine works as a precursor of DA in the human brain. Herein, we report an analytical method that strongly supports the hypothesis that the intake of tyrosine (Tyr)-rich food enhances DA levels. For this analysis, citrate-coated gold-core silver-shell nanoparticles (Au@Ag NPs) were synthesized. The interaction of DA with the Au@Ag NPs was investigated using multiple spectroscopic techniques, and different thermodynamic parameters were evaluated to assign the binding mechanism. Real sample analysis with Tyr-rich food was also conducted to study the effect of Tyr on DA levels. Analytical studies were performed to verify the outcomes of the present work. The limit of detection of the Au@Ag NPs-DA system for Tyr was found to be 1.64 mM. This study can contribute to development in the fields of medicine and pharmaceuticals, particularly in regard to neuromedicine. One of the major advantages of this investigation is that it will fuel research interest in the supplementation of neurotransmitters and help categorize Tyr as a dietary precursor of dopamine.

Gene therapy for neurotransmitter-related disorders.

Inborn errors of neurotransmitter (NT) metabolism are a group of rare, heterogenous diseases with predominant neurological features, such as movement disorders, autonomic dysfunction, and developmental delay. Clinical overlap with other disorders has led to delayed diagnosis and treatment, and some conditions are refractory to oral pharmacotherapies. Gene therapies have been developed and translated to clinics for paediatric inborn errors of metabolism, with 38 interventional clinical trials ongoing to date. Furthermore, efforts in restoring dopamine synthesis and neurotransmission through viral gene therapy have been developed for Parkinson's disease. Along with the recent European Medicines Agency (EMA)and Medicines and Healthcare Products Regulatory Agency (MHRA) approval of an AAV2 gene supplementation therapy for AADC deficiency, promising efficacy and safety profiles can be achieved in this group of diseases. In this review, we present preclinical and clinical advances to address NT-related diseases, and summarise potential challenges that require careful considerations for NT gene therapy studies.

Efficacy and safety of multiple external therapies in patients with insomnia: a systematic review and network meta-analysis.

The annual incidence of insomnia continues to increase owing to changes in lifestyle habits, increased work pressure, and increased environmental pollution. In recent years, an increasing number of external therapies have been proven effective in treating insomnia and have been widely used. However, the relative benefits and harms of external therapies remain uncertain, and an optimal treatment strategy has not yet been determined. A network meta-analysis was performed to evaluate and compare the efficacy and safety of multiple external therapies for patients with insomnia. Eight electronic databases were comprehensively searched from their inception to June 2023 for relevant literature. We also searched the grey literature and reviewed the reference lists of related systematic reviews. Two independent reviewers performed the study selection, data extraction, and bias assessment of the included randomized controlled trials (RCTs) using the Cochrane Reviewers' Handbook, and a network meta-analysis was conducted using Stata and RevMan software. In total, 14,826 studies were identified. Of these, 83 studies, including 9 external therapies and 6,100 patients, were deemed eligible for the present network meta-analysis. Except for the SL outcome, each external therapy was better than conventional medicine and the sham intervention (SI) in improving sleep quality. In terms of improving the psychological state indices of insomnia patients, each external therapy was superior to the SI; each external therapy had a better effect on the regulation of monoamine neurotransmitters. Tuina may be the most effective intervention in improving the total effective rate, Pittsburgh sleep quality index score, and SL. Repetitive transcranial magnetic stimulation (rTMS) perhaps resulted in the best improvement in total sleep time and awakening time (surface under the cumulative ranking curve [SUCRA] = 78.3 and 75.4%, respectively); and moxibustion (MB) and hyperbaric oxygen (HBO) were the most effective in reducing Self-rating Anxiety Scale and Self-rating Depression Scale scores. In terms of improving the monoamine neurotransmitters 5-hydroxytryptamine, norepinephrine, and dopamine, the best interventions were acupoint catgut embedding, electroacupuncture, and Tuina (SUCRA = 82.0, 69.9 and 90.3%, respectively). Safety results showed that the three safest interventions were the SI, Tuina, and foot bath. No serious adverse events were reported across the studies, and the most common minor adverse events included drowsiness, pain, excessive thirst, and hematoma. Both Tuina and rTMS have significant effects on improving sleep quality, but the safety of rTMS is low. Therefore, Tuina can be recommended as the first line of treatment to improve sleep quality. If a patient's anxiety and depression symptoms are evident, MB or HBO can be selected for treatment based on the actual situation. External therapy to improve sleep quality may be related to the regulation of monoamine neurotransmitters, which may be a potential mechanism of action. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=440882.

Pomalidomide Improves Motor Behavioral Deficits and Protects Cerebral Cortex and Striatum Against Neurodegeneration Through a Reduction of Oxidative/Nitrosative Damages and Neuroinflammation After Traumatic Brain Injury.

Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague-Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation.

Parkinson’s New Advancements in Diagnosis and Treatment: A Review

Parkinsonism Disease (PD) is a progressive neurological disorder. Although PD is associated with a variety of Non-motor symptoms (NMS) in virtually all patients including hyposmia, constipation, pain and sleep disturbances. It is age related disorder and affects more than 6 million population every year. It is associated with neuronal degeneration in substantia nigra and to lesser extent, in the globus pallidus, putamen and caudate nucleus. The degeneration of the neurons of the substantia nigra that send their axons to the corpus striatum results in reduction in the release of neurotransmitter dopamine with in corpus striatum. This leads to hypersensitivity of the dopamine receptors in the post synaptic neurons in the striatum. Individuals have characteristics signs and symptoms tremors, bradykinesia, postural instabilities, rigidity. Neither loss of sense nor muscle power is usually seen in such cases. Deep tendon, Superficial and Abdominal reflexes are well retained on evaluation. There has been various types of classification in Parkinsonism which are described later. Together with aging, genetics, environment and the role of biological sex as important factor in development of PD has been widely discussed in the past decade. Investigations in PD remains a challenge, recent studies included 7 Tesla MRI, PET and SPECT have proved to be confirmatory in diagnosis of PD. Parkinsonism disease treatment includes increasing the levels of dopamine in brain by giving its immediate precursor L-dopa which can easily cross blood brain barrier unlike dopamine. Evidence of slowing the process of degeneration has been seen with drug selegiline. Other than drugs surgical options include pallidotomy

Potential Neuroprotective Effect of the Endocannabinoid System on Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by alterations in motor capacity resulting from a decrease in the neurotransmitter dopamine due to the selective death of dopaminergic neurons of the nigrostriatal pathway. Unfortunately, conventional pharmacological treatments fail to halt disease progression; therefore, new therapeutic strategies are needed, and currently, some are being investigated. The endocannabinoid system (ECS), highly expressed in the basal ganglia (BG) circuit, undergoes alterations in response to dopaminergic depletion, potentially contributing to motor symptoms and the etiopathogenesis of PD. Substantial evidence supports the neuroprotective role of the ECS through various mechanisms, including anti-inflammatory, antioxidative, and antiapoptotic effects. Therefore, the ECS emerges as a promising target for PD treatment. This review provides a comprehensive summary of current clinical and preclinical evidence concerning ECS alterations in PD, along with potential pharmacological targets that may exert the protection of dopaminergic neurons.

Facile stoichiometric interfacial surface bonded cerium oxide and graphene oxide heterostructure for efficient electrochemical non-enzymatic detection of dopamine.

Emerging technology in the new era of sensors to detect and quantify neurological reaction-based research has demanded the development of sensors for the neurotransmitter dopamine (DA). In recent decades, electrochemical sensors have offered rapid and sensitive detection of DA, but the presence of interfering compounds, such as uric acid (UA) and ascorbic acid (AA), poses a great threat to the development of DA sensors. Additionally, reusing traditional methods leads to challenges like prolonged preparation and expensive instruments. This research work offers a nanohybrid two-dimensional (2D) paper-like graphene oxide (GO) and three-dimensional (3D) cerium oxide nanosphere (CeONS) heterostructure composite (G-CeONS) created via stoichiometric synthesis for the non-enzymatic detection of DA oxidation in the presence of other complex biological compounds. The constructed G-CeONS nanohybrid composite enables enhanced selectivity and sensitivity towards DA detection through its interfacial engineering. The heterostructure formation of a 2D nanosheet draped over 3D nanospheres exhibits a wide linear concentration range of 100-30 800 nM with a low detection limit of 20.98 nM. Further investigation of the real-time performance on human saliva and DA injections afforded prominent results. In addition, the synergetic effect of G-CeONS improves DA detection accuracy and reliability towards enabling transformational neurochemical and medicinal applications.

Microelectrode Set Made of Carbon Nanotubes for the Detection of Biomolecules and Neurotransmitters

Electrode miniaturization is an alternative path for the development of sensitive electrochemical sensors. The low charging current, enhanced mass transport and their suitability to be employed in resistive mediums has made microelectrodes attractive for detection of biomolecules. Carbon nanotubes (CNTs) are unique nanomaterials with high electrical conductivity and mechanical strength. They are known for their chemical stability and the ability to assemble them into nano and microelectrodes makes them an appealing alternative electrode material compared to metals. This talk will report the fabrication of an electrochemical-set that has CNT microelectrode assemblies as working, reference, and counter electrode components and have been tested for the detection of heavy metals (Pb2+), neurotransmitters (dopamine), and other biomolecules (nicotinamide adenine dinucleotide (NADH), furosemide). Limits of detection of 0.5 nM for dopamine, 18 nM for NADH, 2 nM for Furosemide, and 0.4 ppt for Pb2+ have been achieved. Different voltammetric techniques were employed during the study: cyclic voltammetry (CV), square wave voltammetry (SWV), amperometry, and square wave anodic stripping voltammetry (SWASV). The robustness of the electrodes and the simplicity of its fabrication have been demonstrated. Furthermore, a simple method for the fabrication nanoelectrode arrays that can be employed as working electrodes will be presented. The background and key components that are considered important to achieve this performance will be reported.

(Keynote) Electrochemical and Mass Spectrometry Measurements of Nanometer Vesicles

We originally developed a tool to measure the chemical messenger contents of single nanometer vesicles starting with capillary electrophoretic separation, lysing and electrochemical detection. We called this flow vesicle impact cytometry (FVIEC). The method used a microfluidic device with sheath flow and electrode for detection. The next generation approaches led to static electrochemical measurements and mass spectrometry imaging of vesicular content. First, micro-/nano-electrochemical approaches have been developed to carry out quantitative measurements of intravesicular content and real-time monitoring of vesicle release dynamics. We have used stochastic vesicle impact electrochemical cytometry (VIEC) and intracellular VIEC (IVIEC) to provide a highly effective way to quantify the electroactive contents inside vesicles. This has allowed direct comparison of the quantity of molecules released by exocytosis to those in the vesicles. Partial release is observed across all cell types examined to date by the electrochemical methods and appears to be regulated.More recently, we have used mass spectrometry imaging with NanoSIMS as a complimentary approach to image the neurotransmitter dopamine across the internal volume of these incredibly small vesicular structures. We have developed standards to carry out quantitative NanoSIMS and subsequently used it to quantify the chemical contents across the nanometer structure of vesicles. We then used NanoSIMS imaging of dopamine inside and drug into vesicles to quantify the fraction of messenger and demonstrate drug entry during exocytosis providing definitive evidence of partial release and a means to introduce drug into cells.

Adenosine Receptor mRNA Expression in Frontal Cortical Neurons in Schizophrenia.

Schizophrenia is a devastating neuropsychiatric disorder associated with the dysregulation of glutamate and dopamine neurotransmitter systems. The adenosine system is an important neuroregulatory system in the brain that modulates glutamate and dopamine signaling via the ubiquitously expressed adenosine receptors; however, adenosine A1 and A2A receptor (A1R and A2AR) mRNA expression is poorly understood in specific cell subtypes in the frontal cortical brain regions implicated in this disorder. In this study, we assayed A1R and A2AR mRNA expression via qPCR in enriched populations of pyramidal neurons, which were isolated from postmortem anterior cingulate cortex (ACC) tissue from schizophrenia (n = 20) and control (n = 20) subjects using laser microdissection (LMD). A1R expression was significantly increased in female schizophrenia subjects compared to female control subjects (t(13) = -4.008, p = 0.001). A1R expression was also significantly decreased in female control subjects compared to male control subjects, suggesting sex differences in basal A1R expression (t(17) = 2.137, p = 0.047). A significant, positive association was found between dementia severity (clinical dementia rating (CDR) scores) and A2AR mRNA expression (Spearman's r = 0.424, p = 0.009). A2AR mRNA expression was significantly increased in unmedicated schizophrenia subjects, suggesting that A2AR expression may be normalized by chronic antipsychotic treatment (F(1,14) = 9.259, p = 0.009). Together, these results provide novel insights into the neuronal expression of adenosine receptors in the ACC in schizophrenia and suggest that receptor expression changes may be sex-dependent and associated with cognitive decline in these subjects.

Amphetamine Induces Sex-Dependent Loss of the Striatal Dopamine Transporter in Sensitized Mice.

Dopamine transporter (DAT) controls dopamine signaling in the brain through the reuptake of synaptically released dopamine. DAT is a target of abused psychostimulants such as amphetamine (Amph). Acute Amph administration induces transient DAT endocytosis, which, among other Amph effects on dopaminergic neurons, elevates extracellular dopamine. However, the effects of repeated Amph abuse, leading to behavioral sensitization and drug addiction, on DAT are unknown. Hence, we developed a 14 d Amph-sensitization protocol in knock-in mice expressing HA-epitope-tagged DAT (HA-DAT) and investigated the effects of Amph challenge on sensitized HA-DAT animals. The Amph challenge resulted in the highest locomotor activity on Day 14 in both sexes, which was sustained for 1 h in male but not female mice. Strikingly, significant (by 30-60%) loss of the HA-DAT protein in the striatum was caused by the Amph challenge of sensitized males but not females. Amph also reduced V max of dopamine transport in the striatal synaptosomes of males without changing K m values. Consistently, immunofluorescence microscopy revealed a significant increase of HA-DAT colocalization with the endosomal protein VPS35 only in Amph-challenged males. Amph-induced loss of striatal HA-DAT in sensitized mice was blocked by chloroquine, vacuolin-1, and inhibitor of Rho-associated kinases ROCK1/2, indicative of the involvement of endocytic trafficking in the DAT protein loss. Interestingly, an apparent degradation of HA-DAT protein was observed in the nucleus accumbens and not in the dorsal striatum. We propose that Amph challenge in sensitized mice triggers Rho-mediated endocytosis and post-endocytic trafficking of DAT in a brain-region-specific and sex-dependent manner.

Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice

Dysregulation of dopamine neurotransmission profoundly affects motor, motivation and learning behaviors, and can be observed during the prodromal phase of Parkinson’s disease (PD). However, the mechanism underlying these pathophysiological changes remains to be elucidated. Mutations in vacuolar protein sorting 35 (VPS35) and leucine-rich repeat kinase 2 (LRRK2) both lead to autosomal dominant PD, and VPS35 and LRRK2 may physically interact to govern the trafficking of synaptic cargos within the endo-lysosomal network in a kinase-dependent manner. To better understand the functional role of VPS35 and LRRK2 on dopamine physiology, we examined Vps35 haploinsufficient (Haplo) and Vps35 p.D620N knock-in (VKI) mice and how their behavior, dopamine kinetics and biochemistry are influenced by LRRK2 kinase inhibitors. We found Vps35 p.D620N significantly elevates LRRK2-mediated phosphorylation of Rab10, Rab12 and Rab29. In contrast, Vps35 haploinsufficiency reduces phosphorylation of Rab12. While striatal dopamine transporter (DAT) expression and function is similarly impaired in both VKI and Haplo mice, that physiology is normalized in VKI by treatment with the LRRK2 kinase inhibitor, MLi-2. As a corollary, VKI animals show a significant increase in amphetamine induced hyperlocomotion, compared to Haplo mice, that is also abolished by MLi-2. Taken together, these data show Vps35 p.D620N confers a gain-of-function with respect to LRRK2 kinase activity, and that VPS35 and LRRK2 functionally interact to regulate DAT function and striatal dopamine transmission.

The protective role of l-carnitine on oxidative stress, neurotransmitter perturbations, astrogliosis, and apoptosis induced by thiamethoxam in the brains of male rats

Synthetic organic insecticides such as pyrethroids, organophosphates, neonicotinoids, and others have the potential to disrupt ecosystems and are often toxic to humans. Thiamethoxam (TMX), a neonicotinoid insecticide , is a widely used insecticide with neurotoxic potential. l-Carnitine (LC) is regarded as the “gatekeeper” in charge of allowing long-chain fatty acids into cell mitochondria. LC is an endogenous chemical that is renowned for its prospective biological activity in addition to its role in energy metabolism. This study investigated the protective effects of LC against TMX-induced neurotoxicity in male Wistar rats. For 28 days, animals were divided into four groups and treated daily with either LC (300 mg/kg), TMX (100 mg/kg), or both at the aforementioned doses. Our results revealed marked serum lipid profile and electrolyte changes, declines in brain antioxidants and neurotransmitters (acetylcholine, dopamine, and serotonin levels) with elevations in thiobarbituric acid reactive substances and proinflammatory cytokine levels, as well as acetylcholinesterase and monoamine oxidase brain activity in TMX-treated rats. TMX also increased the expression of caspase-3 and glial fibrillary acidic protein. In contrast, pretreatment with LC attenuated TMX-induced brain injury by suppressing oxidative stress and proinflammatory cytokines and modulating neurotransmitter levels. It also ameliorated the expression of apoptotic and astrogliosis markers. It could be concluded that LC has antioxidant, anti-inflammatory, anti-astrogliosis, and anti-apoptotic potential against TMX neurotoxicity.Graphical abstract

Alkaline liquid-derived NaxTi11.5MoVOx/C-40 material with controlled electron transfer rate for sensitive electrochemical detection of dopamine

The neurotransmitter dopamine (DA) is associated with many physiological and pathological processes, so the importance of low detection limits and high sensitivity analysis cannot be overstated, especially for early disease detection. Here, 2 M NaOH aqueous solution is used to precipitate metal ions in an ethanol solution containing carbon black (CB), and then nanocomposite catalysts (NaxTi11.5MoVOx/C-40 (40 denoted as 40 mg CB)) were obtained by calcining the precipitation. When used for DA detection, NaxVOx acts as the main active site for electrochemical oxidation of DA and NaxTi11.5MoOx plays a role in facilitating the binding of DA to the active site and stabilizing the active site. The NaxTi11.5MoVOx/C-40 electrochemical biosensor has a limit of detection (LOD) of 0.003 μM with a linear range of 0.005–51.665 μM for DA. This sensor can be used to sensitively identify the concentration of DA in human blood and urine. Catalysts containing varying amounts of CB exhibit diverse electron transfer rates, and surprisingly, we found that the appropriate electron transfer rate is optimal for the detection of low concentrations of DA. Because the performance of the electrochemical biosensors is affected by both the activity of the catalysts and the accuracy of the electrochemical testing instrumentation. To better explain this phenomenon, we propose the concept of resolution (Rn) and present the formula to derive it, offering a new approach to evaluating the performance of electrochemical biosensors.

Integration of Magnetic-Field-Directed Self-Assembly-Based Cell Culture and Biosensing Platform for Improving hPSCs-Derived Neurons and Quantitative Detection of Neurotransmitter.

Despite the fact that human neural cell models have played significant roles in both research and cell replacement therapies for neurological diseases, the existing techniques for obtaining neurons from human pluripotent stem cells (hPSCs) are arduous and intricate. Additionally, the evaluation of neuron quality in the natural environment remains deficient. Consequently, we have developed a comprehensive platform utilizing magnetic-field-directed self-assembly (MDSA) of MXenes@Fe3O4 (M/F) nanocomposites. This platform facilitates the cultivation and in situ analysis of differentiated dopaminergic (DA) neurons. Our results showed that the introduction of M/F enhances neurite outgrowth and leads to the development of more intricate ramifications. Moreover, with the increase of magnetic field intensity, neurite outgrowth is further enhanced, and the proportion of differentiated mature neurons from hPSCs increases. This suggests that our platform promotes the maturation of neurons, emphasizing the crucial role of biophysical cues in expediting the differentiation process. The homogenization platform formed by MDSA of M/F nanocomposites exhibits high conductivity, leading to its exceptional performance in the real-time monitoring of the release of dopamine neurotransmitter from hPSC-derived DA neurons. Hence, this platform demonstrates significant potential for monitoring cell quality. In conclusion, our integrated platform, based on MDSA of M/F nanocomposites, offers a reliable and efficient means for the in vitro generation of human neurons with a controllable quality. The as-prepared platform holds potential for enhancing neuronal maturation and ensuring consistent cell quality, showing significant implications for in vitro biological research, disease modeling, and cell replacement therapy.

Leaky lessons learned: Efflux prone dopamine transporter variant reveals sex and circuit specific contributions of D2 receptor signalling to neuropsychiatric disease.

Aberrant dopamine (DA) signalling has been implicated in various neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder (BPD) and addiction. The availability of extracellular DA is sculpted by the exocytotic release of vesicular DA and subsequent transporter-mediated clearance, rendering the presynaptic DA transporter (DAT) a crucial regulator of DA neurotransmission. D2-type DA autoreceptors (D2ARs) regulate multiple aspects of DA homeostasis, including (i) DA synthesis, (ii) vesicular release, (iii) DA neuron firing and (iv) the surface expression of DAT and DAT-mediated DA clearance. The DAT Val559 variant, identified in boys with ADHD or ASD, as well as in a girl with BPD, supports anomalous DA efflux (ADE), which we have shown drives tonic activation of D2ARs. Through ex vivo and in vivo studies of the DAT Val559 variant using transgenic knock-in mice, we have uncovered a circuit and sex-specific capacity of D2ARs to regulate DAT, which consequently disrupts DA signalling and behaviour differently in males and females. Our studies reveal the ability of the construct-valid DAT Val559 model to elucidate endogenous mechanisms that support DA signalling, findings that may be of translational and/or therapeutic importance.