Search Results (2,589)

Cysteamine hydrochloride (Cys-HCl) has been established as a potent ulcerogenic agent of the gastrointestinal (GI) system. GI dysfunction and olfactory deficits are the most common clinical symptoms of many movement disorders, including Parkinson’s disease (PD). Cys-HCl has been shown to interfere with dopamine, a neurotransmitter crucial for motor, olfactory, and cognitive functions. However, the reports on the effect of Cys-HCl treatment on the behavioral aspects and functions of the dopamine system appear to be inconsistent. Therefore, we revisited the impact of Cys-HCl on the motor function in experimental mice using a battery of behavioral tests, such as the pole test (PT), beam-walking test (BWT), and rotarod test (RDT), while the olfactory ability and cognitive functions were examined through the buried-food test (BFT) and Y-maze test. Furthermore, we investigated the effect of Cys-HCl on the number of dopaminergic tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) and olfactory bulb (OB) of the experimental mice using immunohistochemistry. The results revealed that Cys-HCl administration in the mice induced significant impairments in their motor balance and coordination, as their movement-related performances were markedly reduced in terms of the behavioral tasks. Mice exposed to Cys-HCl showed pronounced reductions in their odor discrimination abilities as well as cognitive impairments. Strikingly, the number of TH-positive neurons was found to be reduced in the SN and OB of the Cys-HCl-treated group, which is a bonafide neuropathogenic hallmark of PD. This study highlights the potential neurotoxic effects of Cys-HCl in experimental brains and suggests further investigation into its role in the pathogenesis of Parkinsonism. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms due to the loss of dopamine-producing neurons and the presence of Lewy bodies in the brain. While current treatments such as dopamine replacement with levodopa and deep brain stimulation mainly manage symptoms and do not stop disease progression, recent advancements in nanomedicine provide promising new therapy options. These include drug-loaded nanocarriers that improve drug delivery to the brain, enhancing effectiveness and reducing side effects. This review explores novel nanomedical approaches like solid lipid nanocarriers (SLNs), which could improve drug profiles and decrease the adverse effects seen with traditional PD treatments. Additionally, it discusses the challenge of crossing the blood–brain barrier, which is crucial for treating central nervous system disorders, and how nanocarriers facilitate targeted brain delivery. Despite these advancements, the review emphasizes more research into the safety and long-term impacts of nanomedicine in PD, highlighting the challenge of moving these treatments from lab to clinical use. Full article

Parkinson’s disease (PD) is a progressive neurological disorder that is typically characterized by a range of motor dysfunctions, and its impact extends beyond physical abnormalities into emotional well-being and cognitive symptoms. The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) leads to an array of dysfunctions in the functioning of the basal ganglia (BG) circuitry that manifests into PD. While active research is being carried out to find the root cause of SNc cell death, various therapeutic techniques are used to manage the symptoms of PD. The most common approach in managing the symptoms is replenishing the lost dopamine in the form of taking dopaminergic medications such as levodopa, despite its long-term complications. Another commonly used intervention for PD is deep brain stimulation (DBS). DBS is most commonly used when levodopa medication efficacy is reduced, and, in combination with levodopa medication, it helps reduce the required dosage of medication, prolonging the therapeutic effect. DBS is also a first choice option when motor complications such as dyskinesia emerge as a side effect of medication. Several studies have also reported that though DBS is found to be effective in suppressing severe motor symptoms such as tremors and rigidity, it has an adverse effect on cognitive capabilities. Henceforth, it is important to understand the exact mechanism of DBS in alleviating motor symptoms. A computational model of DBS stimulation for motor symptoms will offer great insights into understanding the mechanisms underlying DBS, and, along this line, in our current study, we modeled a cortico-basal ganglia circuitry of arm reaching, where we simulated healthy control (HC) and PD symptoms as well as the DBS effect on PD tremor and bradykinesia. Our modeling results reveal that PD tremors are more correlated with the theta band, while bradykinesia is more correlated with the beta band of the frequency spectrum of the local field potential (LFP) of the subthalamic nucleus (STN) neurons. With a DBS current of 220 pA, 130 Hz, and a 100 microsecond pulse-width, we could found the maximum therapeutic effect for the pathological dynamics simulated using our model using a set of parameter values. However, the exact DBS characteristics vary from patient to patient, and this can be further studied by exploring the model parameter space. This model can be extended to study different DBS targets and accommodate cognitive dynamics in the future to study the impact of DBS on cognitive symptoms and thereby optimize the parameters to produce optimal performance effects across modalities. Combining DBS with rehabilitation is another frontier where DBS can reduce symptoms such as tremors and rigidity, enabling patients to participate in their therapy. With DBS providing instant relief to patients, a combination of DBS and rehabilitation can enhance neural plasticity. One of the key motivations behind combining DBS with rehabilitation is to expect comparable results in motor performance even with milder DBS currents. Full article

The mesolimbic pathway connects ventral tegmental area dopaminergic neurons and striatal medium spiny neurons, playing a critical role in reward and stress behaviors. Exposure to substances of abuse during development and adulthood has been linked to adverse outcomes and molecular changes. The rise of human cell repositories and whole-genome sequences enables human functional genomics ‘in a dish’, offering insights into human-specific responses to substances of abuse. Continued development of new models is needed, and the characterization of in vitro models is also necessary to ensure appropriate experimental designs and the accurate interpretation of results. This study introduces new culture conditions for generating medium spiny neurons and dopaminergic neurons with an early common media, allowing for coculture and assembloid generation. It then provides a comprehensive characterization of these and prior models and their responses to substances of abuse. Single-cell analysis reveals cell-type-specific transcriptomic responses to dopamine, cocaine, and morphine, including compound and cell-type-specific transcriptomic signatures related to neuroinflammation and alterations in signaling pathways. These findings offer a resource for future genomics studies leveraging human stem cell-derived models. Full article

This article reports a simple hydrothermal method for synthesizing nickel disulfide (NiS₂) on the surface of fluorine-doped tin oxide (FTO) glass, followed by the deposition of 5 nm Au nanoparticles on the electrode surface by physical vapor deposition. This process ensures the uniform distribution of Au nanoparticles on the NiS₂ surface to enhance its conductivity. Finally, an Au@NiS₂-FTO electrochemical biosensor is obtained for the detection of dopamine (DA). The composite material is characterized using transmission electron microscopy (TEM), UV-Vis spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The electrochemical properties of the sensor are investigated using cyclic voltammetry (CV), differential pulse voltammetry (DPV), and time current curves in a 0.1 M PBS solution (pH = 7.3). In the detection of DA, Au@NiS₂-FTO exhibits a wide linear detection range (0.1~1000 μM), low detection limit (1 nM), and fast response time (0.1 s). After the addition of interfering substances, such as glucose, L-ascorbic acid, uric acid, CaCl₂, NaCl, and KCl, the electrode potential remains relatively unchanged, demonstrating its strong anti-interference capability. It also demonstrates strong sensitivity and reproducibility. The obtained Au@NiS₂-FTO provides a simple and easy-to-operate example for constructing nanometer catalysts with enzyme-like properties. These results provide a promising method utilizing Au coating to enhance the conductivity of transition metal sulfides. Full article

Ultra-processed foods (UPFs) like pastries, packaged snacks, fast foods, and sweetened beverages have become dominant in the modern food supply and are strongly associated with numerous public health concerns. While the physical health consequences of UPF intake have been well documented (e.g., increased risks of cardiometabolic conditions), less empirical discussion has emphasized the mental health consequences of chronic UPF consumption. Notably, the unique characteristics of UPFs (e.g., artificially high levels of reinforcing ingredients) influence biological processes (e.g., dopamine signaling) in a manner that may contribute to poorer psychological functioning for some individuals. Importantly, gold-standard behavioral lifestyle interventions and treatments specifically for disordered eating do not acknowledge the direct role that UPFs may play in sensitizing reward-related neural functioning, disrupting metabolic responses, and motivating subsequent UPF cravings and intake. The lack of consideration for the influences of UPFs on mental health is particularly problematic given the growing scientific support for the addictive properties of these foods and the utility of ultra-processed food addiction (UPFA) as a novel clinical phenotype endorsed by 14–20% of individuals across international samples. The overarching aim of the present review is to summarize the science of how UPFs may affect mental health, emphasizing contributing biological mechanisms. Specifically, the authors will (1) describe how corporate-sponsored research and financial agendas have contributed to contention and debate about the role of UPFs in health; (2) define UPFs and their nutritional characteristics; (3) review observed associations between UPF intake and mental health conditions, especially with depression; (4) outline the evidence for UPFA; and (5) describe nuanced treatment considerations for comorbid UPFA and eating disorders. Full article

Two-dimensional MXenes have become an important material for electrochemical sensing of biomolecules due to their excellent electric properties, large surface area and hydrophilicity. However, the simultaneous detection of multiple biomolecules using MXene-based electrodes is still a challenge. Here, a simple solvothermal process was used to synthesis the Ti₃C₂T_x coated with TiO₂ nanosheets (Ti₃C₂T_x@TiO₂ NSs). The surface modification of TiO₂ NSs on Ti₃C₂T_x can effectively reduce the self-accumulation of Ti₃C₂T_x and improve stability. Glassy carbon electrode was modified by Ti₃C₂T_x@TiO₂ NSs (Ti₃C₂T_x@TiO₂ NSs/GCE) and was able simultaneously to detect dopamine (DA), ascorbic acid (AA) and uric acid (UA). Under concentrations ranging from 200 to 1000 μM, 40 to 300 μM and 50 to 400 μM, the limit of detection (LOD) is 2.91 μM, 0.19 μM and 0.25 μM for AA, DA and UA, respectively. Furthermore, Ti₃C₂T_x@TiO₂ NSs/GCE demonstrated remarkable stability and reliable reproducibility for the detection of AA/DA/UA. Full article

Glial cell line-derived neurotrophic factor (GDNF) is among the strongest dopamine neuron function- and survival-promoting factors known. Due to this reason, it has clinical relevance in dopamine disorders such as Parkinson’s disease and schizophrenia. In the striatum, GDNF is exclusively expressed in interneurons, which make up only about 0.6% of striatal cells. Despite clinical significance, histological analysis of striatal GDNF system arborization and relevance to incoming dopamine axons, which bear its receptor RET, has remained enigmatic. This is mainly due to the lack of antibodies able to visualize GDNF- and RET-positive cellular processes; here, we overcome this problem by using knock-in marker alleles. We find that GDNF neurons chemoattract RET+ axons at least seven times farther in distance than medium spiny neurons (MSNs), which make up 95% of striatal neurons. Furthermore, we provide evidence that tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, is enriched towards GDNF neurons in the dopamine axons. Finally, we find that GDNF neuron arborizations occupy approximately only twelve times less striatal volume than 135 times more abundant MSNs. Collectively, our results improve our understanding of how endogenous GDNF affects striatal dopamine system function. Full article

This study aimed to test the hypothesis that the postactivation effect (PAE, involuntary normal muscle tone) is modified by dopaminergic mechanisms. The PAE was tested with surface electromyography (sEMG) in the “off medication” phase in participants with Parkinson’s disease (PD_off) and in the “on medication” state in participants with schizophrenia (SZ_on), which modeled hypodopaminegic conditions, and in participants with PD “on medication” (PD_on) and in participants with SZ “off medication” (SZ_off) state which modeled the hyperdopaminergic conditions. Healthy age-matched participants constituted the control group (HC, n = 11). In hyperdopaminergic models, PAE was triggered in 71.3% of participants in SZ_off and in 35.7% in PD_on conditions. In the hypodopaminergic models, PAE was triggered in 12% in SZ_on and in 21.4% in PD_off conditions. In the HC group, PAE was present in 91% of participants. In the HC and PD groups, the mean frequency and correlation dimension of sEMG at PAE was higher than that during voluntary isometric contraction. In conclusion, in hypodopaminergic models, PAE triggering was inhibited. The manifestations and EMG characteristics of PAE in people with PD or SZ may indicate dopaminergic dysfunction. Full article

Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. The hippocampal formation is known to participate in memory and learning processes and has been documented to contribute to opioid dependence. Accordingly, the present study assessed molecular and cellular alterations in the hippocampal formation of Wistar rats intraperitoneally administered with 50 mg/kg tramadol or tapentadol for eight alternate days. Alterations were found in serum hydrogen peroxide, cysteine, homocysteine, and dopamine concentrations upon exposure to one or both opioids, as well as in hippocampal 8-hydroxydeoxyguanosine and gene expression levels of a panel of neurotoxicity, neuroinflammation, and neuromodulation biomarkers, assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of hippocampal formation sections showed increased glial fibrillary acidic protein (GFAP) and decreased cluster of differentiation 11b (CD11b) protein expression, suggesting opioid-induced astrogliosis and microgliosis. Collectively, the results emphasize the hippocampal neuromodulator effects of tramadol and tapentadol, with potential behavioral implications, underlining the need to prescribe and use both opioids cautiously. Full article

Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT. Full article

Chronic migraine is a disabling disorder without effective therapeutic medicine. AMPA receptors have been proven to be essential to pathological pain and headaches, but the related regulatory mechanisms in chronic migraine have not yet been explored. In this study, we found that the level of surface GluA2 was reduced in chronic migraine rats. Tat-GluR23Y (a GluA2 endocytosis inhibitor) reduced calcium inward flow and weakened synaptic structures, thus alleviating migraine-like pain sensitization. In addition, the inhibition of GluA2 endocytosis reduced the calcium influx and alleviated mitochondrial calcium overload and ROS generation in primary neurons. Furthermore, our results showed that ROS can induce allodynia and GluA2 endocytosis in rats, thus promoting migraine-like pain sensitization. In our previous study, the dopamine D2 receptor was identified as a potential target in the treatment of chronic migraine, and here we found that dopamine D2 receptor activation suppressed chronic-migraine-related pain sensitization through blocking the GluA2/ROS positive feedback loop in vivo and in vitro. Additionally, ligustrazine, a core component of ligusticum chuanxiong, was shown to target the dopamine D2 receptor, thereby alleviating ROS production and abnormal nociception in CM rats. This study provides valuable insight into the treatment of chronic migraine. Full article

In this study, a facile approach for simultaneous determination of dopamine (DA) and tryptophan (TRP) using a 3D goethite–spongin-modified carbon paste electrode is reported. The prepared electrode exhibited excellent electrochemical catalytic activity towards DA and TRP oxidation. The electrochemical sensing of the modified electrode was investigated using cyclic voltammetry, differential pulse voltammetry, and electrochemical impedance spectroscopy. Through differential pulse voltammetry analysis, two well-separated oxidation peaks were observed at 28 and 77 mV, corresponding to the oxidation of DA and TRP at the working electrode, with a large peak separation of up to 490 mV. DA and TRP were determined both individually and simultaneously in their dualistic mixture. As a result, the anodic peak currents and the concentrations of DA and TRP were found to exhibit linearity within the ranges of 4–246 μM for DA and 2 to 150 μM for TRP. The detection limits (S/N = 3) as low as 1.9 μM and 0.37 μM were achieved for DA and TRP, respectively. The proposed sensor was successfully applied to the simultaneous determination of DA and TRP in human urine samples with satisfactory recoveries (101% to 116%). Full article

Background: Schizophrenia is a mental disorder affecting approximately 0.32% of the global population, according to the World Health Organization. Antipsychotic medications are used to treat this condition by inhibiting D2 dopamine and 5HT2 serotonin receptors. The selection of the appropriate mode of delivery for these drugs is based on factors such as patient adherence, clinical presentation, and patient preferences. However, additional drivers of treatment selection are required in clinical practice. Mounting evidence suggests that neuroinflammation plays a crucial role in the pathogenesis of schizophrenia. NLR, a cost-effective biomarker of inflammation, has increased in several psychiatric conditions and may represent a valid method for studying the inflammatory stage in schizophrenia, relapse, and the first episode of psychosis. The aim of this study is to evaluate whether there are any variations in NLR values between patients given oral antipsychotics and those given long-acting antipsychotics. Methods: The study included 50 individuals with schizophrenia, either acute or in the follow-up phase. NLR was obtained by calculating the ratio of absolute neutrophil count (cells/μL) and absolute lymphocyte count (cells/μL). Results: Patients on long-acting antipsychotics exhibited significantly lower mean NLR scores (1.5 ± 0.7) compared to those on oral antipsychotics (2.2 ± 1.3) (p < 0.05). Conclusions: NLR appears promising as a neuroinflammatory biomarker. This study reveals significantly lower NLR values in patients on long-acting antipsychotics, which may signify reduced systemic inflammation and improved adherence. Full article

This study aimed to assess the expression profile of messenger RNA (mRNA) and microRNA (miRNA) related to the dopaminergic system in five types of breast cancer in Polish women. Patients with five breast cancer subtypes were included in the study: luminal A (n = 130), luminal B (n = 196, including HER2−, n = 100; HER2+, n = 96), HER2+ (n = 36), and TNBC (n = 43); they underwent surgery, during which tumor tissue was removed along with a margin of healthy tissue (control material). The molecular analysis included a microarray profile of mRNAs and miRNAs associated with the dopaminergic system, a real-time polymerase chain reaction preceded by reverse transcription for selected genes, and determinations of their concentration using enzyme-linked immunosorbent assay (ELISA). The conducted statistical analysis showed that five mRNAs statistically significantly differentiated breast cancer sections regardless of subtype compared to control samples; these were dopamine receptor 2 (DRD2), dopamine receptor 3 (DRD3), dopamine receptor 25 (DRD5), transforming growth factor beta 2 (TGF-β-2), and caveolin 2 (CAV2). The predicted analysis showed that hsa-miR-141-3p can regulate the expression of DRD2 and TGF-β-2, whereas hsa-miR-4441 is potentially engaged in the expression regulation of DRD3 and DRD5. In addition, the expression pattern of DRD5 mRNA can also be regulated by has-miR-16-5p. The overexpression of DRD2 and DRD3, with concomitant silencing of DRD5 expression, confirms the presence of dopaminergic abnormalities in breast cancer patients. Moreover, these abnormalities may be the result of miR-141-3P, miR-16-5p, and miR-4441 activity, regulating proliferation or metastasis. Full article